WO2024033458A1 - Dérivés bicycliques de tétrahydroazépine - Google Patents

Dérivés bicycliques de tétrahydroazépine Download PDF

Info

Publication number
WO2024033458A1
WO2024033458A1 PCT/EP2023/072129 EP2023072129W WO2024033458A1 WO 2024033458 A1 WO2024033458 A1 WO 2024033458A1 EP 2023072129 W EP2023072129 W EP 2023072129W WO 2024033458 A1 WO2024033458 A1 WO 2024033458A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
oxadiazol
dihydro
benzazepin
trifluoro
Prior art date
Application number
PCT/EP2023/072129
Other languages
English (en)
Inventor
Marco BRANDSTAETTER
Holger Kuehne
Thomas Luebbers
Laetitia Janine MARTIN
Original Assignee
F. Hoffmann-La Roche Ag
Hoffmann-La Roche Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by F. Hoffmann-La Roche Ag, Hoffmann-La Roche Inc. filed Critical F. Hoffmann-La Roche Ag
Publication of WO2024033458A1 publication Critical patent/WO2024033458A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to bicyclic tetrahydroazepine compounds which inhibit Diacylglycerol kinases (DGK) a and C, and are useful as T-Cell activators, their manufacture and pharmaceutical compositions comprising said compounds.
  • DGK Diacylglycerol kinases
  • the present compounds may be useful as immunotherapeutic agents for the treatment of human diseases. More specifically, the present compounds can be used alone or in combination with other immunotherapeutic agents in order to boost anti-cancer immunity.
  • Cancer immunity is a multistep process that is regulated by a series of negative immune checkpoint and positive co-stimulatory receptors and related intracellular signaling cascades that when effectively triggered can achieve antitumor response (Mellman, I., et al. (2011) Cancer Immunotherapy Comes of Age, Nature 480(7378), 480-489). Indeed, PD1/PDL1 targeting and other immune-checkpoint inhibitors have revolutionized cancer immunotherapy, but still more than 70% of patients do not benefit from immune-checkpoint inhibition. Similarly, for T-cell bispecific antibodies, even in the most promising indication (Non-Hodgkin lymphoma), these T-cell binders (TCBs) achieve complete remissions in less than 50% of patients.
  • T-cell exhaustion seems to play an important role in many of these examples of primary or secondary resistance to cancer immunotherapy.
  • a possible reason for this lack of efficacy is that T-cell activation occurs via targeting and crosslinking of CD3 (signal 1), but co- stimulation e.g. via CD28 or 4-1BB (signal 2) is missing. This hypothesis was verified clinically for CAR T-cell therapy where it was shown that only after the incorporation of co- stimulatory domains, clinically relevant efficacy was observed.
  • DGKs Diacylglycerol kinases
  • DAG Diacylglycerol
  • PA phosphatidic acid
  • the DGK family consist of ten isoforms that can be grouped into five subtypes based on the presence of different regulatory domains within their structure. Beyond that, the lack of structural data as of now still hinders a more thorough understanding of the DGKs mode of action.
  • DGK ⁇ and C have been extensively characterized as negative regulators of T cell responses (Riese, M.J., Moon, E.K., Johnson, B.D., Albelda, S.M., 2016. Diacylglycerol kinases (DGKs): novel targets for improving T cell activity in cancer. Front Cell Dev Biol 4,108; Noessner, E., 2017.
  • DGK- alpha a checkpoint in cancer -mediated immuno-inhibition and target for immunotherapy.
  • Biological regulation of diacylglycerol kinases in normal and neoplastic tissues New opportunities for cancer immunotherapy, Advances in Biological Regulation, Volume 75).
  • DGK ⁇ and DGK ⁇ are active downstream of CD28 and other costimulatory receptors as well as the T cell receptor (TCR), and their function is to limit the amount of DAG generated - and ultimately T-cell activation (Merida, I., Andrada, E., Gharbi,
  • Activated PLCI cleaves PIP2 in the plasma membrane to generate two secondary messengers, DAG and IP3.
  • DAG activates PKC, Ras/MEK/ERK/AP-1 and NF-kB, while IP3 is involved in the activation of intracellular Ca2+ flux.
  • the upregulated Ca2+ signaling in turn activates the transcription factor NF AT.
  • DAG production and levels determine the duration and intensity of the Ras/MEK/ERK and PKC-dependent signaling pathways, and they are central to T-cell activation.
  • DGKs serve as intracellular checkpoints and inhibition of DGKs is expected to enhance T cell signaling pathways and T cell activation.
  • TILs tumor infiltrating T-cells
  • CAR T cells directed against human mesothelioma engrafted into nude mice demonstrated that tumorinfiltrating CAR T cells express elevated concentrations of surface inhibitory receptors, as well as the inhibitory enzymes SHIP-1, DGK ⁇ and DGK ⁇ (Moon et al., 2014). Further, high DGK ⁇ expression was also observed in TIL isolated from human renal tumors (Prinz et al., 2012).
  • DGKs Diacylglycerol kinases
  • mice lacking either DGK ⁇ or DGK ⁇ showed a hyper- responsive T cell phenotype and improved anti-tumor immune activity (Riese, M.J., Grewal, J., Das, J., Zou, T., Patil, V., Chakraborty, A.K., Koretzky, G.A., 2011. Decreased diacylglycerol metabolism enhances ERK activation and augments CD8+ T cell functional responses. J. Biol. Chem.
  • T cell anergy is reversed by active Ras and is regulated by diacylglycerol kinase-alpha. Nat. Immunol. 7 (11), 1166— 1173; Olenchock, B.A., Guo, R., Carpenter, J.H., Jordan, M., Topham, M.K., Koretzky, G.A., Zhong, X.P., 2006a. Disruption of diacylglycerol metabolism impairs the induction of T cell anergy. Nat. Immunol. 7 (11), 1174-1181.)
  • This invention describes such dual DGK ⁇ / ⁇ inhibitors with excellent selectivity over other protein kinases, across safety / off-target panels and vs. other lipid kinases. These compounds potently activate suboptimally stimulated T-cells and thereby act as intracellular enhancers of co- stimulatory signaling cascades. These DGK ⁇ / ⁇ inhibitors have the potential to increase proliferation, cytotoxicity and the life span of targeted T-cells which may result in improved anticancer activity of CPIs, CD3 engaging T-cell bispecifics and CAR T-cells. Further, by engaging a signaling node central to both TCR and co-stimulatory receptors, it is plausible that these molecules enhance both signals 1 and 2 and thus single agent activity can be achieved, e.g. in inflamed tumors.
  • an object of this invention to provide compounds useful as DGK ⁇ / ⁇ inhibitors for the treatment or prevention or amelioration of such diseases with improved therapeutic properties, in particular improved pharmacokinetic properties.
  • a first object of the present invention is a compound of formula (I) or a pharmaceutically accep ,
  • R 1 is 5 or 6-membered heteroaryl, wherein R 1 is optionally substituted with one or more R 10 which can be the same or different;
  • R 2 is selected from hydrogen and halogen;
  • R 4 is selected from phenyl and pyridinyl, wherein R 4 is optionally substituted with one or more R 11 which can be the same or different;
  • R 10 is selected from: i) C1-6-alkyl, optionally substituted with one or more halogen, amino, C1-6-alkoxy, - S(O) 2 (C 1-6 -alkyl), cyano; ii) C3-10-cycloalkyl, optionally substituted with one or more halogen, cyano, amino; iii) 3-10 membered heterocyclyl, optionally substituted with one or more halogen, C1-10- alkyl, amino, halo-C
  • a second object of the present invention is a process for the preparation of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, comprising reacting a compound of formula (XVIII) wherein R 1 , R 2 and R 4 are a cting group, with a suitable deprotection agent to form said compound of formula (I).
  • a third object of the present invention is a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a forth object of the present invention is a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment, prevention and/or delay of progression of cancer.
  • the alkoxy group contains 1 to 12 carbon atoms (“C1-12-alkoxy”), preferably 1 to 10 carbon atoms (“C1-10-alkoxy”), more preferably 1 to 6 carbon atoms (“C1-6-alkoxy”). In some preferred embodiments, the alkoxy group contains 1 to 4 carbon atoms. In still other embodiments, the alkoxy group contains 1 to 3 carbon atoms. Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n- propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy.
  • Alkoxyalkyl refers toan alkyl group, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by an alkoxy group.
  • alkoxyalkyl refers to an alkyl group wherein 1, 2 or 3 hydrogen atoms, most preferably one hydrogen atom of the alkyl group have been replaced by an alkoxy group.
  • Particularly preferred, yet non-limiting examples of alkoxyalkyl is methoxymethyl and 2-methoxyethyl.
  • Alkyl refers to a saturated linear (i.e.
  • alkyl groups are those having 1 to 20 carbon atoms (a “C1- 20 alkyl”), having 1 to 12 carbon atoms (a “C 1 - 12 alkyl”), having 1 to 10 carbon atoms (a “C 1 - 10 alkyl”), having 1 to 8 carbon atoms (a “C1-8 alkyl”), having 1 to 6 carbon atoms (a “C1-6 alkyl”), having 2 to 6 carbon atoms (a “C2-6 alkyl”), or having 1 to 4 carbon atoms (a “C1-4 alkyl”).
  • alkyl group examples include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
  • Alkynyl refers to an unsaturated linear (i.e.
  • alkynyl groups are those having 2 to 20 carbon atoms (a “C 2-20 alkynyl”), having 2 to 8 carbon atoms (a “C 2-8 alkynyl”), having 2 to 6 carbon atoms (a “C2-6 alkynyl”), having 2 to 4 carbon atoms (a “C2-4 alkynyl”).
  • alkynyl group examples include, but are not limited to, groups such as ethynyl (or acetylenyl), prop-1-ynyl, prop-2-ynyl (or propargyl), but-1-ynyl, but-2-ynyl, but-3-ynyl, homologs and isomers thereof, and the like.
  • Amino alone or in combination with other groups, refers to NH2.
  • Aminoalkyl refers to an alkyl group wherein one or more of the hydrogen atoms of the alkyl group have been replaced by an amino moiety.
  • Aryl refers to a cyclic aromatic hydrocarbon moiety having a mono-, bi- or tricyclic aromatic ring of 5 to 14 carbon ring atoms (“C5-14-aryl”).
  • Bicyclic aryl ring systems include fused bicyclics having two fused five-membered aryl rings (denoted as 5-5), having a five- membered aryl ring and a fused six-membered aryl ring (denoted as 5-6 and as 6-5), and having two fused six-membered aryl rings (denoted as 6-6).
  • the aryl group can be optionally substituted as defined herein. Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, and the like.
  • aryl also includes partially hydrogenated derivatives of the cyclic aromatic hydrocarbon moiety provided that at least one ring of the cyclic aromatic hydrocarbon moiety is aromatic, each being optionally substituted.
  • Cancer refers to a disease characterized by the presence of a neoplasm or tumor resulting from abnormal uncontrolled growth of cells (such cells being “cancer cells”).
  • cancer explicitly includes, but is not limited to, hepatocellular cancer, malignancies and hyperproliferative disorders of the colon (colon cancer), lung cancer, breast cancer, prostate cancer, melanoma, and ovarian cancer.
  • Cyano alone or in combination with other groups, refers to CN (i.e. nitrile).
  • Cyanoalkyl refers to an alkyl group wherein one or more of the hydrogen atoms of the alkyl group have been replaced by a cyano moiety.
  • Cycloalkyl refers to a saturated or partially unsaturated carbocyclic moiety having mono-, bi- (including bridged bicyclic and cycloalkyl spiro moieties) or tricyclic rings and 3 to 10 carbon atoms i.e., (C3-C10)cycloalkyl) in the ring.
  • the cycloalkyl moiety can optionally be substituted with one or more substituents.
  • cycloalkyl contains from 3 to 8 carbon atoms (i.e., (C3-C8)cycloalkyl). In other particular aspects cycloalkyl contains from 3 to 6 carbon atoms (i.e., (C3-C6)cycloalkyl).
  • cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and partially unsaturated (cycloalkenyl) derivatives thereof (e.g.
  • cyclopentenyl, cyclohexenyl, and cycloheptenyl bicyclo[3.1.0]hexanyl, bicyclo[3.1.0]hexenyl, bicyclo[3.1.1]heptanyl, bicyclo[3.1.1]heptenyl and bicyclo[1.1.1]pentane.
  • the cycloalkyl moiety can be attached in a “spiro-cycloalkyl” or “cycloalkyl spiro” fashion such as “spirocyclopropyl” .
  • "EC x " refers to the effective concentration e.g. in medium or in the plasma of a particular compound required for obtaining x% of the maximum of a particular effect in vitro or in vivo.
  • ECx examples are EC20, EC50 and EC100 denoting the concentration of a particular compound in medium or plasma required for obtaining 20%, 50% and 100%, respectively, of the maximum of a particular effect in vitro or in vivo.
  • Halo or “Halogen” refers to fluoro, chloro, bromo and/or iodo. Where a residue is substituted with more than one halogen, it can be referred to by using a prefix corresponding to the number of halogen moieties attached, e.g., dihaloaryl, dihaloalkyl, trihaloaryl etc.
  • Haloalkyl refers to aryl and alkyl substituted with two (“di”) or three (“tri”) Halo groups, which can be but are not necessarily the same Halo; thus 4-chloro-3-fluorophenyl is within the scope of dihaloaryl.
  • An alkyl group in which one or more hydrogen is replaced with a Halo group is referred to as a “haloalkyl”, for example, “C1-6 haloalkyl.”
  • a preferred haloalkyl group is trifluoroalkyl (-CF3).
  • Haloalkoxy refers to an alkoxy group in which at least one halogen takes the place of each H in the hydrocarbon making up the alkyl moiety of the alkoxy group.
  • haloalkoxy group is difluoromethoxy (-OCHF2), trifluoromethoxy (-OCF3).
  • Hydroaryl refers to refers to an aryl wherein at least one hydrogen has been substituted with an halogen.
  • Heteroaryl refers to an aromatic heterocyclic mono-, bi- or tricyclic ring system of 5 to 14 ring atoms, preferably from 5 to 10 ring atoms, more preferably from 5 to 6 ring atoms, comprising 1, 2, 3 or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon. In some aspects, monocyclic heteroaryl rings may be 5-6 membered.
  • Bicyclic heteroaryl ring systems include fused bicyclics having two fused five-membered heteroaryl rings (denoted as 5-5), having a five-membered heteroaryl ring and a fused six-membered heteroaryl ring (denoted as 5-6 and 6-5), and having two fused six-membered heteroaryl rings (denoted as 6-6).
  • the heteroaryl group can be optionally substituted as defined herein.
  • heteroaryl moieties include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothienyl, benzothiophenyl, indolyl, aza-indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzooxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl,
  • heterocycle refers to a 3, 4, 5, 6, 7, 8, 9, 10-membered monocyclic, 7, 8, 9 and 10-membered bicyclic (including bridged bicyclic and cycloalkyl spiro moieties) or 10, 11, 12, 13, 14 and 15-membered bicyclic heterocyclic moiety that is saturated or partially unsaturated, and has one or more (e.g., 1, 2, 3 or 4 heteroatoms selected from oxygen, nitrogen and sulfur in the ring with the remaining ring atoms being carbon.
  • the heterocycle is a heterocycloalkyl.
  • heterocycle or heterocyclyl refers to a 4, 5, 6 or 7-membered heterocycle.
  • a nitrogen or sulfur may also be in an oxidized form, and a nitrogen may be substituted with one or more (C1-C6)alkyl or groups.
  • the heterocycle can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. Any of the heterocycle ring atoms can be optionally substituted with one or more substituents described herein.
  • saturated or partially unsaturated heterocycles include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, pyrrolidine 1-oxide, N-hydroxypiperidine, 1- methylpyrrolidine N-oxide, diazirinyl and quinuclidinyl.
  • heterocycle also includes groups in which a heterocycle is fused to one or more aryl, heteroaryl, or cycloalkyl rings, such as indolinyl, 3H-indolyl, chromanyl, azabicyclo[2.2.1]heptanyl, azabicyclo[3.1.0]hexanyl, azabicyclo[3.1.1]heptanyl, octahydroindolyl, or tetrahydroquinolinyl.
  • “Hydroxy” alone or in combination with other groups, refers to OH.
  • Hydroalkyl refers to an alkyl group wherein one or more of the hydrogen atoms of the alkyl group have been replaced by a hydroxy moiety. Examples include alcohols and diols.
  • Moiety and “substituent” refer to an atom or group of chemically bonded atoms that is attached to another atom or molecule by one or more chemical bonds thereby forming part of a molecule. When indicating the number of substituents, the term “one or more” refers to the range from one substituent to the highest possible number of substitution, i.e.
  • substituents can be the same or different.
  • “Oxo”, alone or in combination with other groups, refers to O.
  • “Pharmaceutically acceptable salt” refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable.
  • the salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, particularly hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcystein.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, particularly hydrochloric acid
  • organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic
  • Particularly preferred pharmaceutically acceptable salts of compounds of formula (I) are the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and methanesulfonic acid.
  • protecting group denotes the group which selectively blocks a reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site in the meaning conventionally associated with it in synthetic chemistry.
  • Protective groups can be removed at the appropriate point.
  • Exemplary protective groups are amino-protective groups, carboxy-protective groups or hydroxy- protective groups.
  • Particular protective groups are the tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc) and benzyl (Bn). Further particular protective groups are the tert-butoxycarbonyl (Boc) and the fluorenylmethoxycarbonyl (Fmoc). More particular protective group is the tert-butoxycarbonyl (Boc). Exemplary protective groups and their application in organic synthesis are described, for example, in “Protective Groups in Organic Chemistry” by T. W. Greene and P. G. M. Wutts, 5th Ed., 2014, John Wiley & Sons, N.Y.
  • “Prophylaxis” as used herein includes: preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a mammal and especially a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition.
  • “Substituted” refers to the replacement of at least one of hydrogen atoms of a compound or moiety with another substituent or moiety. Examples of such substituents include, without limitation, halogen, -OH, -CN, oxo, alkoxy, alkyl, alkylene, aryl, heteroaryl, haloalkyl, haloalkoxy, cycloalkyl and heterocycle.
  • haloalkyl refers to the fact that one or more hydrogen atoms of an alkyl (as defined below) is replaced by one or more halogen atoms (e.g., trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, etc.).
  • substituted as used herein can refer to replacement of at least one hydrogen atom of a compound or moiety described herein with halogen or alkyl.
  • “Therapeutically effective amount” refers to an amount of a compound or molecule of the present invention that, when administered to a subject, (i) treats or prevents the particular disease, condition or disorder, (ii) attenuates, ameliorates or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition or disorder described herein.
  • the therapeutically effective amount will vary depending on the compound, the disease state being treated, the severity of the disease treated, the age and relative health of the subject, the route and form of administration, the judgement of the attending medical or veterinary practitioner, and other factors.
  • “Therapeutically inert carrier” refers to any ingredient having no therapeutic activity and being non-toxic such as disintegrators, binders, fillers, solvents, buffers, tonicity agents, stabilizers, antioxidants, surfactants or lubricants used in formulating pharmaceutical products.
  • the chemical groups whose definitions are given above are those specifically exemplified in the examples.
  • BOP benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate
  • Brine saturated aqueous NaCl solution
  • CAS chemical abstracts registration number
  • CDI 1,1'-Carbonyldiimidazole
  • DAD diode-array detection
  • DBU 1,8-diazabicyclo[5,4,0]undec- 7-ene
  • DCM dichloromethane
  • DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
  • DMF N,N-dimethylformamide
  • DIPEA N,N-diisopropylethylamine
  • EDC 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide
  • ESI electrospray ionization
  • EtOAc ethyl acetate
  • EtOH ethyl acetate
  • EtOH e
  • the depicted structure controls. Additionally, if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold wedged, or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it. In some cases, however, where more than one chiral center exists, the structures and names may be represented as single enantiomers to help describe the relative stereochemistry.
  • a compound of the formula” or “a compound of formula” or “compounds of the formula” or “compounds of formula” refer to any compound selected from the genus of compounds as defined by the formula (including any pharmaceutically acceptable salt of any such compound if not otherwise noted). Certain compounds may exhibit tautomerism. Tautomeric compounds can exist as two or more interconvertable species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium and attempts to isolate an individual tautomers usually produce a mixture whose chemical and physical properties are consistent with a mixture of compounds. The position of the equilibrium is dependent on chemical features within the molecule.
  • keto form predominates while; in phenols, the enol form predominates.
  • the invention includes all optical isomers, i.e. diastereoisomers, diastereomeric mixtures, racemic mixtures, all their corresponding enantiomers and/or tautomers as well as their solvates of the compounds of formula (I).
  • the compounds of formula (I) may contain one or more asymmetric centers and can therefore occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within this invention.
  • the present invention is meant to encompass all such isomeric forms of these compounds.
  • the independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein.
  • Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated.
  • optically pure enantiomer means that the compound contains > 90% of the desired isomer by weight, particularly > 95% of the desired isomer by weight, or more particularly > 99% of the desired isomer by weight, said weight percent based upon the total weight of the isomer(s) of the compound.
  • Chirally pure or chirally enriched compounds may be prepared by chirally selective synthesis or by separation of enantiomers. The separation of enantiomers may be carried out on the final product or alternatively on a suitable intermediate.
  • the compounds of formula (I) are isotopically-labeled by having one or more atoms therein replaced by an atom having a different atomic mass or mass number. Such isotopically-labeled (i.e., radiolabeled) compounds of formula (I) are considered to be within the scope of this disclosure.
  • isotopes that can be incorporated into the compounds of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, and iodine, such as, but not limited to, 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I, respectively.
  • Certain isotopically-labeled compounds of formula (I) for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e.
  • a compound of formula (I) can be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99 percent of a given isotope.
  • Substitution with heavier isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.
  • Substitution with positron emitting isotopes, such as 11 C, 18 F, 15 O and 13 N can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
  • R 1 is 5 or 6-membered heteroaryl, wherein R 1 is optionally substituted with one or more R 10 which can be the same or different;
  • R 2 is selected from hydrogen and halogen;
  • R 4 is selected from phenyl and pyridinyl, wherein R 4 is optionally substituted with one or more R 11 which can be the same or different;
  • R 10 is selected from: i) C1-6-alkyl, optionally substituted with one or more halogen, amino, C1-6-alkoxy, - S(O)2(C1-6-alkyl), cyano; ii) C3-10-cycloalkyl, optionally substituted with one or more halogen, cyano, amino; iii) 3-10 membered heterocyclyl, optionally substituted with one or more halogen, C1-10- alkyl, amino, halo
  • R 1 is oxadiazole, optionally substituted with one or more R 10 which can be the same or different.
  • R 1 is 1,3,4-oxadiazole, substituted with one R 10 .
  • R 2 is fluorine.
  • R 4 is phenyl.
  • a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof wherein R 10 is selected from methyl-methylsulfonyl- ethyl, pyrrolidin, 4-oxa-7-azaspiro[2.5]octan-7-yl, methyl-propanenitrile, 1,2,2,2-tetrafluoro- methoxy-ethyl, tertbutyl, 1-ethyl-5,5-difluoro-3-piperidyl, 4,4-difluoro-1-piperidyl and azabicyclo[3.1.1]heptane-3-carboxylate.
  • a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof wherein R 11 is selected from 5-(trifluoromethyl)-2- pyridyl, phenoxy, trifluoromethoxy, methoxy-pyridyl, cyclopentoxy, 4-methoxyphenyl, (trifluoromethyl)-1,2,4-oxadiazol-3-yl, 5-(trifluoromethoxy)-2-pyridyl, 4- (trifluoromethyl)pyrazol-1-yl, chloro, 5-(difluoromethoxy)-2-pyridyl, 4-[4- (trifluoromethoxy)pyrazol-1-yl, 4-[5-(trifluoromethyl)tetrazol-2-yl.
  • R 1 is 5-membered heteroaryl, wherein R 1 is optionally substituted with one or more R 10 which can be the same or different;
  • R 2 is halogen;
  • R 4 is phenyl or pyridinyl;
  • R 10 is selected from: iv) C1-6-alkyl, optionally substituted with one or more halogen, C1-6-alkoxy, -S(O)2(C1-6- alkyl), cyano;
  • R 11 is selected from: i
  • R 1 is 5-membered heteroaryl, wherein R 1 is optionally substituted with one or more R 10 which can be the same or different;
  • R 2 is halogen;
  • R 4 is phenyl;
  • R 10 is selected from: i) C1-6-alkyl, optionally substituted with one or more halogen, amino, C1-6-alkoxy, - S(O)2(C1-6-alkyl), cyano; ii) C3-10-cycloalkyl, optionally substituted with one or more halogen, cyano, amino; iii) 3-10 membered heterocyclyl, optionally substituted with one or more -C(O)O-(R 10q );
  • R 11 is selected from i) halogen; ii) 5-6 membered heteroaryl, optionally substituted with one or more halogen, halo-C1-6- alkyl, C
  • R 1 is 1,3,4-oxadiazole, substituted with one R 10 ;
  • R 2 is fluorine;
  • R 4 is phenyl;
  • R 10 is selected from methyl-methylsulfonyl-ethyl, pyrrolidin, 4-oxa-7-azaspiro[2.5]octan-7-yl, methyl-propanenitrile, 1,2,2,2-tetrafluoro-methoxy-ethyl, tertbutyl, 1-ethyl-5,5-difluoro-3- piperidyl, 4,4-difluoro-1-piperidyl and azabicyclo[3.1.1]heptane-3-carboxylate;
  • R 11 is selected from 5-(trifluoromethyl)-2-pyridyl, phenoxy, trifluoromethoxy, methoxy- pyridyl, cyclopen
  • R 1 is 5-membered heteroaryl, wherein R 1 is optionally substituted with one or more R 10 which can be the same or different;
  • R 2 is fluorine;
  • R 4 is phenyl;
  • R 10 is selected from difluoro-(methoxyethyl)piperidyl, azabicyclo[3.1.1]heptane-carboxylate, amino-trifluoro-methyl-ethyl, methyl-methylsulfonyl-ethyl, pyrrolidin, oxa- azaspiro[2.5]octanyl, methyl-propanenitrile, tert-butyl, tetrafluoro-methoxy-ethyl, morpholino;
  • R 11 is selected from methoxyphenyl, (trifluoromethyl)-pyridyl, cyclopentoxy, phenoxy, tri
  • R 1 is 1,3,4-oxadiazole, substituted with one R 10 ;
  • R 2 is fluorine;
  • R 4 is phenyl;
  • R 10 is selected from methyl-methylsulfonyl-ethyl, pyrrolidin, oxa-azaspiro[2.5]octanyl, methyl- propanenitrile, tetrafluoro-methoxy-ethyl;
  • R 11 is selected from (trifluoromethyl)-pyridyl, phenoxy, trifluoromethoxy, (trifluoromethyl)- oxadiazolyl, methoxy-pyridyl.
  • a compound of formula (I) as described herein wherein the compound is selected from: 3-amino-8-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5,5,7-trifluoro-1-[[4- (trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-2-one; 2-methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4- dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; 2-methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4- dihydro-1-benzazepin-8-yl]
  • a compound of formula (I) as described herein wherein the compound is selected from: 2-methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4- dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; 2-methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4- dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; (3S)-3-amino-5,5,7-trifluoro-8-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,3,
  • a compound of formula (I) as described herein wherein the compound is selected from: 2-methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4- dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; 2-methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4- dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; (3S)-3-amino-5,5,7-trifluoro-8-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,
  • Processes of manufacturing Processes for the manufacture of compounds of formula (I), or pharmaceutically acceptable salts thereof, as described herein are also an object of the invention.
  • the present invention provides a process for the preparation of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, comprising reacting a compound of formula (XVIII) I) wherein R 1 , R 2 and R 4 are as protecting group, with a suitable deprotection agent to form said compound of formula (I).
  • the preparation of compounds of formula (I) of the present invention may be carried out in sequential or convergent synthetic routes. Syntheses of the invention are shown in the following general schemes. The skills required for carrying out the reaction and purification of the resulting products are known to those persons skilled in the art.
  • compounds of formula (I) can be obtained as mixtures of diastereomers or enantiomers, which can be separated by methods well known in the art e.g., chiral HPLC, chiral SFC or chiral crystallization. Racemic compounds can e.g., be separated into their antipodes via diastereomeric salts by crystallization with optically pure acids or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbent or a chiral eluent. It is equally possible to separate starting materials and intermediates containing stereogenic centers to afford diastereomerically/enantiomerically enriched starting materials and intermediates.
  • the solvent there is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent.
  • the described reactions can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. It is convenient to carry out the described reactions in a temperature range between -78 °C to reflux.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 hours to several days will usually suffice to yield the described intermediates and compounds.
  • reaction sequence is not limited to the one displayed in the schemes, however, depending on the starting materials and their respective reactivity, the sequence of reaction steps can be freely altered. If starting materials or intermediates are not commercially available or their synthesis not described in literature, they can be prepared in analogy to existing procedures for close analogues or as outlined in the experimental section. Processes for the manufacture of compounds of formula (I) as described herein are also an object of the invention. The preparation of compounds of formula (I) of the present invention may be carried out following sequential or convergent synthetic routes. Syntheses of the invention are shown in the following general schemes. The substituents and indices used in the following description of the processes have the significance given herein before unless indicated to the contrary.
  • the compounds of formula (I) can be manufactured by the methods given below, by the methods given in the examples or by analogous methods.
  • Appropriate reaction conditions for the individual reaction steps are known to a person skilled in the art.
  • the reaction sequence is not limited to the one displayed in the schemes, however, depending on the starting materials and their respective reactivity the sequence of reaction steps can be freely altered.
  • Starting materials are either commercially available or can be prepared by methods analogous to the methods given below, by methods described in references cited in the description or in the examples, or by methods known in the art.
  • the present compounds of formula (I) and their pharmaceutically acceptable salts may be prepared by a process described below (Scheme (IX) () (VI) () 1) (V (II)) (V) (VIII) () () () () () () () () () () () () () () () () () Suit (Ia) wbhleere sinta Rr1t iisn 1g,3, m4 (-XoaVxtae)driaiazo Scheme 1 llsl for the preparation of compoun (XdVsI) of formula (I) are aniline derivatives of formula (II).
  • Compounds of formula (II) can be converted into compounds of formula (III) by reaction with chloroacetonitrile in the presence of AlCl3 and BCl3 in a solvent such as toluene at elevated temperatures.
  • Derivatives (III) can be reacted with aminomalonate derivatives (IV) (wherein R n is alkyl) in the presence of sodium iodide and a base such as sodium alkoxide in an alcoholic solvent to obtain compounds of formula (V).
  • Reaction of formula (V) compounds with aqueous HCl at elevated temperatures provides amino acid derivatives of formula (VI) that can subsequently be N-protected by reaction with di-t-butyldicarbonate in a solvent mixture such as dioxane and water in the presence of a base such as TEA to obtain compounds of formula (VII).
  • Derivatives (VII) can be cyclized to compounds of formula (VIII) pierng T3P in presence of a base such as DIPEA or TEA in a solvent such as DCM or THF.
  • a benzyl substituent to obtain compounds of formula (X) can be accomplished by reaction with formula (IX) halides or sulfonates (X 1 is Cl, Br, I or OSO2R) in presence of a base such as K2CO3 in a solvent such as DMF.
  • a base such as K2CO3
  • potassium iodide can be added.
  • Reaction of compounds of formula (X) with DAST provides derivatives of formula (XI) which can be converted into formula (XII) compounds by carbonylation reaction employing catalysts such as Pd(OAc)2/dppp or Pd(dppp)Cl2 in the presence of a base such as TEA or DIPEA in a solvent mixture of DMF and an alcohol at elevated temperatures.
  • acid derivatives (XIII) can be obtained from compounds of formula (XI) by carbonylation reaction employing catalysts such as Pd(OAc)2/dppp or Pd(dppp)Cl2 in the presence of a base such as TEA or DIPEA in a solvent mixture of DMF and water at elevated temperatures.
  • Conversion of compounds of formula (XIII) into compounds of formula (XIV) can be accomplished by reaction with hydrazine after activation of derivatives (XIII) with reagents such as T3P in the presence of DIPEA or oxalyl chloride in the presence of DIPEA and catalytic amounts of DMF in a solvent such as DCM.
  • reagents such as T3P in the presence of DIPEA or oxalyl chloride in the presence of DIPEA and catalytic amounts of DMF in a solvent such as DCM.
  • Activation of compounds of formula (XIV) with reagents such as HATU or T3P in the presence of a base such as DIPEA and subsequent reation with an acid derivative R 10 CO2H provides compounds of formula (XV).
  • compounds of formula (XV) can be obtained from compounds of formula (XIII) by reaction with hydrazide derivatives R 10 CONHNH 2 and a coupling reagent such as HATU in the presence of a base such as DIPEA in a solvent such as THF.
  • Formula (XVI) compounds can be obtained from compounds of formula (XV) by reaction with dehydrating agents such as Burgess reagent in a solvent such as toluene or THF.
  • Compounds of formula (I, wherein R 1 is 1,3,4-oxadiazolyl) can be obtained from compounds of formula (XVI) by reaction with HCl in EtOAc, TFA in DCM or HFIP.
  • Compounds of formula (XVIII) can be converted into compounds of formula (I) wherein R 1 is a 6-membered heteroaryl group as described for the conversion of compounds of formula (XVI) to compounds of formula (I) in scheme 1.
  • Pharmaceutical compositions and administration Another object of the present invention is a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicaments, in the form of pharmaceutical preparations.
  • the pharmaceutical preparations can be administered internally, such as orally (e.g.
  • the administration can also be effected parenterally, such as intramuscularly or intravenously (e.g. in the form of injection solutions).
  • the administration can also be effected topically, e.g. transdermal administration, or in form of eye drops or ear drops.
  • the compounds of formula (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations, such as tablets, coated tablets, dragées, hard gelatin capsules, injection solutions or topical formulations.
  • Lactose, corn starch or derivatives thereof, talc, stearic acids or salts thereof, and the like can be used, for example, as such carriers for tablets, coated tablets, dragées and hard gelatin capsules.
  • Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols and the like. Depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatin capsules.
  • Suitable carriers for the production of solutions and syrups are, for example, water, alcohols, polyols, saccharose, glucose, invert sugar, vegetable oil, etc.
  • Suitable carriers for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.
  • Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, etc.
  • Suitable carriers for topical ocular formulations are, for example, cyclodextrins, mannitol or many other carriers and excipients known in the art.
  • the pharmaceutical preparations can contain preservatives, solubilizers, viscosity increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain other therapeutically valuable substances.
  • Medicaments containing a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient are also an object of the present invention, as is a process for their production, which comprises bringing one or more compounds of formula (I) and/or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more pharmaceutically acceptable excipients.
  • the dosage can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case.
  • the formulation can contain 0.001% to 15% by weight of medicament and the required dose, which can be between 0.1 and 25 mg, and can be administered either by single dose per day or per week, or by multiple doses (2 to 4) per day, or by multiple doses per week.
  • the pharmaceutical composition according to the invention may be prepared as follows. Preparation of pharmaceutical compositions comprising compounds of the invention Tablet Formulation (Wet Granulation) 5) Magnesium Stearate 1 2 2 5 Total 200 200 300 600 Manufacturing Procedure: 1. Mix ingredients 1, 2 and 3 in a suitable mixer for 30 minutes. 2. Add ingredients 4 and 5 and mix for 3 minutes. 3. Fill into a suitable capsule. Injection Solutions Ingredient mg/injection solution Compound of formula I 3 Polyethylene Glycol 400 150 acetic acid q.s.
  • a compound of formula (I) is dissolved in a mixture of Polyethylene Glycol 400 and water for injection (part). The pH is adjusted to 5.0 by acetic acid. The volume is adjusted to 1.0 ml by addition of the residual amount of water. The solution is filtered, filled into vials using an appropriate overage and sterilized. Indications The compounds of formula (I) can be used in an effective amount to treat a subject, in particular a human, affected by cancer. In one aspect, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable thereof, for use as a therapeutically active substance.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable thereof, for use in the treatment, prevention and/or delay of progression of cancer.
  • the present invention provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the treatment, prevention and/or delay of progression of cancer.
  • the present invention provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment, prevention and/or delay of progression of cancer.
  • the present invention provides a method for the treatment, prevention and/or delay of progression of cancer, which method comprises administering a therapeutically effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof.
  • treatment or “treating” and grammatical variations thereof as used herein, is meant therapeutic therapy.
  • treating means: (1) to ameliorate the condition or one or more of the biological manifestations of the condition, (2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the condition or (b) one or more of the biological manifestations of the condition, (3) to alleviate one or more of the symptoms, effects or side effects associated with the condition or treatment thereof, or (4) to slow the progression of the condition or one or more of the biological manifestations of the condition.
  • Prophylactic therapy using the methods and/or compositions of the invention is also contemplated. The skilled artisan will appreciate that "prevention" is not an absolute term.
  • prevention is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof.
  • Prophylactic therapy is appropriate, for example, when a subject is considered at high risk for developing cancer, such as when a subject has a strong family history of cancer or when a subject has been exposed to a carcinogen.
  • immunotherapeutic agents acting on immune cells rather than directly acting on the cancer cells, the present disclosure could also be foreseen for the use as anti-cancer vaccines. This also comprises approaches in which immune cells are cultured and manipulated ex vivo and the herein disclosed molecules are used as a way of conferring co-stimulation of the ex vivo manipulated cells.
  • the cancer is a hematologic cancer such as lymphoma, a leukemia or a myeloma.
  • a hematologic cancer contemplated herein includes, but is not limited to, one or more leukemias such as B-cell acute lymphoid leukemia ("BALL”), T-cell acute lymphoid leukemia (“TALL”), acute lymphoid leukemia (ALL); one or more chronic leukemias including but not limited to chronic myelogenous leukemia (CML) and chronic lymphocytic leukemia (CLL); additional hematologic cancers or hematologic conditions including, but not limited to B cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt's lymphoma, diffuse large B cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell- or a large cell-follicular lymphoma, malignant lymphoproliferative
  • the cancer is a non-hematologic cancer such as a sarcoma, a carcinoma, or a melanoma.
  • a non-hematologic cancer contemplated herein includes, but is not limited to, a neuroblastoma, renal cell carcinoma, colon cancer, colorectal cancer, breast cancer, epithelial squamous cell cancer, melanoma, stomach cancer, brain cancer, lung cancer (e.g. non- small cell lung cancer - NSCLC), pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, prostate cancer, testicular cancer, thyroid cancer, uterine cancer, adrenal cancer and head and neck cancer.
  • Co-administration of compounds of formula (I) and other agents may be employed alone or in combination with other agents for treatment.
  • the second agent of the pharmaceutical combination formulation or dosing regimen may have complementary activities to the compound of formula (I) such that they do not adversely affect each other.
  • the compounds may be administered together in a unitary pharmaceutical composition or separately.
  • a compound or a pharmaceutically acceptable salt can be co-administered with a cytotoxic agent to treat proliferative diseases and cancer.
  • co-administering refers to either simultaneous administration, or any manner of separate sequential administration, of a compound of formula (I) or a salt thereof or a compound disclosed herein or a pharmaceutically acceptable salt thereof and a further active pharmaceutical ingredient or ingredients, including cytotoxic agents and radiation treatment. If the administration is not simultaneous, the compounds are administered in a close time proximity to each other. Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g. one compound may be administered topically and another compound may be administered orally. Typically, any agent that has anti-cancer activity may be co-administered. Examples of such agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S.
  • the present invention provides a pharmaceutical composition described herein, further comprising an additional therapeutic agent.
  • said additional therapeutic agent is a chemotherapeutic agent.
  • said additional therapeutic agent is a cytotoxic agent.
  • said additional therapeutic agent is an immuno-oncology agent.
  • cytotoxic agent refers to a substance that inhibits or prevents a cellular function and/or causes cell death or destruction.
  • Cytotoxic agents include, but are not limited to, radioactive isotopes (At 211 , I 131 , I 125 , Y 90 , Re 186 , Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212 and radioactive isotopes of Lu); chemotherapeutic agents; growth inhibitory agents; enzymes and fragments thereof such as nucleolytic enzymes; and toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and/or variants thereof.
  • Exemplary cytotoxic agents can be selected from anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, inhibitors of LDH-A; inhibitors of fatty acid biosynthesis; cell cycle signaling inhibitors; HDAC inhibitors, proteasome inhibitors; and inhibitors of cancer metabolism.
  • “Chemotherapeutic agent” includes chemical compounds useful in the treatment of cancer.
  • chemotherapeutic agents include erlotinib (TARCEVA®, Genentech/OSI Pharm.), bortezomib (VELCADE®, Millennium Pharm.), disulfiram , epigallocatechin gallate , salinosporamide A, carfilzomib, 17-AAG(geldanamycin), radicicol, lactate dehydrogenase A (LDH-A), fulvestrant (FASLODEX®, AstraZeneca), sunitib (SUTENT®, Pfizer/Sugen), letrozole (FEMARA®, Novartis), imatinib mesylate (GLEEVEC®., Novartis), finasunate (VATALANIB®, Novartis), oxaliplatin (ELOXATIN®, Sanofi), 5-FU (5-fluorouracil), leucovorin, Rapamycin (Sirolimus, RAPAMUNE®, Wyeth), Lapatin
  • dynemicin including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino- doxorubicin and deoxydoxorubicin), epirubicin,
  • Chemotherapeutic agent also includes (i) anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, iodoxyfene , 4-hydroxytamoxifen, trioxifene, keoxifene,LYl 17018, onapristone, and FARESTON® (toremifine citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer), formestanie, fadrozole, RIVISOR® (vorozole), FEMARA® (let
  • Chemotherapeutic agent also includes antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen pie), pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia), and the antibody drug conjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth).
  • antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RIT
  • Additional humanized monoclonal antibodies with therapeutic potential as agents in combination with the compounds of the invention include: apolizumab, aselizumab, atlizumab, bapineuzumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizum
  • Chemotherapeutic agent also includes “EGFR inhibitors,” which refers to compounds that bind to or otherwise interact directly with EGFR and prevent or reduce its signaling activity, and is alternatively referred to as an “EGFR antagonist.” Examples of such agents include antibodies and small molecules that bind to EGFR.
  • antibodies which bind toEGFR include MAb 579 (ATCC CRL HB 8506), MAb 455 (ATCC CRL HB8507), MAb 225 (ATCC CRL 8508), MAb 528 (ATCC CRL 8509) (see, US Patent No.4,943, 533, Mendelsohn et al.) and variants thereof, such as chimerized 225 (C225 or Cetuximab; ERBUTIX®) and reshaped human 225 (H225) (see, WO 96/40210, Imclone Systems Inc.); IMC-11F8, a fully human, EGFR-targeted antibody (Imclone); antibodies that bind type II mutant EGFR (US Patent No.5,212,290); humanized and chimeric antibodies that bind EGFR as described in US Patent No.5,891,996; and human antibodies that bind EGFR, such as ABX-EGF or Panitumumab (see WO98/50433, Abgenix
  • EMD7200 a humanized EGFR antibody directed against EGFR that competes with both EGF and TGF-alpha for EGFR binding
  • human EGFR antibody HuMax-EGFR (GenMab)
  • Fully human antibodies known as El.l, E2.4, E2.5, E6.2, E6.4, E2.ll, E6.3 and E7.6.3 and described in US 6,235,883; MDX-447 (Medarex Inc); and mAb 806 or humanized mAb 806 (Johns et al, J. Biol. Chem.279(29):30375-30384 (2004)).
  • the anti-EGFR antibody may be conjugated with a cytotoxic agent, thus generating an immunoconjugate (see, e.g., EP659,439A2, Merck Patent GmbH).
  • EGFR antagonists include small molecules such as compounds described in US Patent Nos: 5,616,582, 5,457,105,5,475,001, 5,654,307, 5,679,683, 6,084,095, 6,265,410, 6,455,534, 6,521,620, 6,596,726, 6,713,484, 5,770,599, 6,140,332, 5,866,572, 6,399,602, 6,344,459, 6,602,863, 6,391,874, 6,344,455, 5,760,041, 6,002,008, and 5,747,498, as well as the following PCT publications: W098/14451, W098/50038, W099/09016, and WO99/24037.
  • EGFRantagonists include OSI-774 (CP-358774, erlotinib, TARCEVA® Genentech/OSI Pharmaceuticals); PD 183805 (Cl 1033, 2-propenamide, N-[4-[(3-chloro-4- fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-, dihydrochloride, Pfizer Inc.); ZD1839, gefitinib (IRESSA®) 4-(3’-Chloro-4’-fluoroanilino)-7-methoxy-6-(3- morpholinopropoxy)quinazoline, AstraZeneca); ZM 105180 ((6-amino-4-(3-methylphenyl- amino)-quinazoline, Zeneca); BIBX-1382 (N8-(3-chloro-4-fluoro-phenyl)-N2-(l-methyl- pipe
  • Chemotherapeutic agents also include “tyrosine kinase inhibitors” including the EGFR- targeted drugs noted in the preceding paragraph; small molecule FIER2 tyrosine kinase inhibitor such as TAK165 available from Takeda; CP-724,714, an oral selective inhibitor of the ErbB2 receptor tyrosine kinase (Pfizer and OSI); dual-HER inhibitors such as EKB-569 (available from Wyeth) which preferentially binds EGFR but inhibits both HER2 and EGFR- overexpressing cells; lapatinib (GSK572016; available from Glaxo-SmithKline), an oral HER2 and EGFR tyrosine kinase inhibitor; PKI-166 (available from Novartis); pan-HER inhibitors such as canertinib (CI-1033; Pharmacia); Raf-I inhibitors such as antisense agent ISIS-5132 available from ISIS Pharmaceuticals which inhibit Raf-I signaling; non-HER targeted
  • Chemotherapeutic agents also include dexamethasone, interferons, colchicine, metoprine, cyclosporine, amphotericin, metronidazole, alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic trioxide, asparaginase, BCG live, bevacuzimab, bexarotene, cladribine, clofarabine, darbepoetin alfa, denileukin, dexrazoxane, epoetin alfa, elotinib, filgrastim, histrelin acetate, ibritumomab, interferon alfa-2a, interferon alfa-2b, lenalidomide, levamisole, mesna, methoxsalen, nandrolone, nelarabine, nofetumomab, oprelvekin,
  • Chemotherapeutic agents also include hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone-17-butyrate, hydrocortisone-17-valerate, aclometasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone- 17-butyrate, clobetasol-17-propionate, fluocortolone caproate, fluocortolone pivalate and fluprednidene acetate; immune
  • celecoxib or etoricoxib proteosome inhibitor
  • CCI-779 tipifamib (R11577); orafenib, ABT510
  • Bcl-2 inhibitor such as oblimersen sodium (GENASENSE®)
  • pixantrone famesyltransferase inhibitors such as lonafamib (SCH 6636, SARASARTM)
  • pharmaceutically acceptable salts, acids or derivatives of any of the above as well as combinations of two or more of the above such as CHOP, an abbreviation for a combined therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone
  • FOLFOX an abbreviation for a treatment regimen with oxaliplatin (ELOXATINTM) combined with 5-FU and leucovorin.
  • ELOXATINTM oxaliplatin
  • compounds of formula (I) can be co-formulated with an immuno- oncology agent.
  • Immuno-oncology agents include, for example, a small molecule drug, antibody, or other biologic or small molecule.
  • biologic immuno-oncology agents include, but are not limited to, cancer vaccines, antibodies, and cytokines.
  • the antibody is a monoclonal antibody.
  • the monoclonal antibody is humanized or human.
  • the antibody is a bispecific antibody.
  • the immuno-oncology agent is (i) an agonist of a stimulatory (including a co-stimulatory) receptor or (ii) an antagonist of an inhibitory (including a co-inhibitory) signal on T cells, both of which result in amplifying antigen-specific T cell responses (often referred to as immune checkpoint regulators).
  • a stimulatory and inhibitory molecules are members of the immunoglobulin super family (IgSF).
  • B7 family includes B7-1, B7-2, B7-H1 (PD- L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6.
  • TNF family of molecules that bind to cognate TNF receptor family members which includes CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL/Apo2-L, TRAILR1/DR4, TRAILR2/DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR/Fnl4, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTfiR, LIGHT, DcR3, HVEM, VEGI/TL1A, TRAMP/DR3, EDAR, EDA1, XEDAR, EDA2,TNFRl, Lymphotoxin ⁇ / ⁇ , TNFR2, TNF a, LT R, Lymphotoxin a 1 ⁇ 2, FAS
  • T cell responses can be stimulated by a combination of a compound of formula (I) and one or more of (i) an antagonist of a protein that inhibits T cell activation (e.g., immune checkpoint inhibitors) such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin 9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4, and (ii) an agonist of a protein that stimulates T cell activation such as B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3 and CD28H.
  • an antagonist of a protein that inhibits T cell activation e.g., immune check
  • agents that can be combined with compounds of formula (I) for the treatment of cancer include antagonists of inhibitory receptors on NK cells or agonists of activating receptors on NK cells.
  • compounds of formula (I) can be combined with antagonists of KIR, such as lirilumab.
  • agents for combination therapies include agents that inhibit or deplete macrophages or monocytes, including but not limited to CSF-1R antagonists such as CSF-1R antagonist antibodies including RG7155 or FPA-008.
  • compounds of formula (I) can be used with one or more of agonistic agents that ligate positive costimulatory receptors, blocking agents that attenuate signaling through inhibitory receptors, antagonists, and one or more agents that increase systemically the frequency of anti-tumor T cells, agents that overcome distinct immune suppressive pathways within the tumor microenvironment (e.g., block inhibitory receptor engagement (e.g., PD-Ll/PD- 1 interactions), deplete or inhibit Tregs (e.g., using an anti-CD25 monoclonal antibody (e.g., daclizumab) or by ex vivo anti-CD25 bead depletion), inhibit metabolic enzymes such as IDO, or reverse/prevent T cell anergy or exhaustion) and agents that trigger innate immune activation and/or inflammation at tumor sites.
  • agonistic agents that ligate positive costimulatory receptors e.g., blocking agents that attenuate signaling through inhibitory receptors, antagonists, and one or more agents that increase system
  • the immuno-oncology agent is a CTLA-4 antagonist, such as an antagonistic CTLA-4 antibody.
  • Suitable CTLA-4 antibodies include, for example, YERVOY (ipilimumab) or tremelimumab.
  • the immuno-oncology agent is a PD-1 antagonist, such as an antagonistic PD-1 antibody.
  • Suitable PD-1 antibodies include, for example, OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MEDI-0680 (AMP-514; WO2012/145493).
  • the immuno-oncology agent may also include pidilizumab (CT-011), though its specificity for PD-1 binding has been questioned.
  • the immuno-oncology agent is a PD-L1 antagonist, such as an antagonistic PD-L1 antibody.
  • Suitable PD-L1 antibodies include, for example, TECENTRIQ (atezolizumab) (RG7446; WO2010/077634), durvalumab (MEDI4736), BMS-936559 (WO2007/005874), and MSB0010718C (WO2013/79174).
  • the immuno-oncology agent is a LAG-3 antagonist, such as an antagonistic LAG-3 antibody.
  • Suitable LAG3 antibodies include, for example, BMS-986016 (WO2010/19570, WO2014/08218), or IMP-731 or IMP-321 (WO2008/132601, WO2009/44273).
  • the immuno-oncology agent is a CD137 (4-1BB) agonist, such as an agonistic CD137 antibody.
  • Suitable CD137 antibodies include, for example, urelumab and PF- 05082566 (WO2012/32433).
  • the immuno-oncology agent is a GITR agonist, such as an agonistic GITR antibody.
  • Suitable GITR antibodies include, for example, BMS-986153, BMS-986156, TRX-518 (WO2006/105021, WO2009/009116) and MK-4166 (WO20l1/028683).
  • the immuno-oncology agent is an IDO antagonist. Suitable IDO antagonists include, for example, INCB-024360 (WO2006/122150, WO2007/75598, WO2008/36653, WO2008/36642), indoximod, or NLG-919 (WO2009/73620, WO2009/1156652, WO2011/56652, WO2012/142237).
  • the immuno-oncology agent is an OX40 agonist, such as an agonistic OX40 antibody.
  • Suitable OX40 antibodies include, for example, MEDI-6383 or MEDI-6469.
  • the immuno-oncology agent is an OX40L antagonist, such as an antagonistic OX40 antibody. Suitable OX40L antagonists include, for example, RG-7888 (WO06/029879).
  • the immuno-oncology agent is a CD40 agonist, such as an agonistic CD40 antibody.
  • the immuno-oncology agent is a CD40 antagonist, such as an antagonistic CD40 antibody.
  • Suitable CD40 antibodies include, for example, lucatumumab or dacetuzumab.
  • the immuno-oncology agent is a CD27 agonist, such as an agonistic CD27 antibody. Suitable CD27 antibodies include, for example, varlilumab.
  • the immuno-oncology agent is MGA271 (to B7H3) (WO20l1/109400).
  • Step b) 1-ethyl-5,5-difluoro-piperidine-3-carboxylic acid
  • THF a solution of methyl 1-ethyl-5,5-diflu 3-carboxylate (340.0 mg, 1.64 mmol, 1.0 eq) in THF (10 mL)
  • LiOH monohydrate 131.26 mg, 3.28 mmol, 2.0 eq
  • water 2 mL
  • the mixture was poured into water (10 mL) and the pH was adjusted to 5 by addition of HCl (1 M).
  • the miture was then lyophilized to give a white solid (300 mg) containing the title compound.
  • thionyl chloride (1.39 mL, 19.11 mmol, 3.0 eq) at 25°C and the mixture was stirred at 25°C for 1 h.
  • step b 2-[4-(chloromethyl)phenyl]-5-(1,1-difluoroethyl)pyridine
  • the title compound was prepared in a 3, step b from [4-[5-(difluoromethyl)- 2-pyridyl]phenyl]methanol and was obtained as light yellow solid.
  • Step b) 2-[4-(chloromethyl)phenyl]-5-(difluoromethoxy)pyridine The title compound was prepared in enyl]methanol and was obtained as ligh Nt yello O 3, step b from [4-[5-(difluoromethox -pyridyl]ph C y)- 2 l Fw so Flid. MS (ESI): 270.0 [M+H] + .
  • Step b) 3,5-dibromo-1-(p-tolyl)-4-(trifluoromethoxy)pyrazole and 5-bromo-1-(p-tolyl)-4- (trifluoromethoxy)pyrazole A solution of 1,3-dibrom 2 mg, 30.26 mmol, 4.0 eq) and HF-pyridine (1165.27 mg, 7.57 mmol, 1.0 eq) in DCM (15 mL) was stirred at -70°C for 0.5 h.
  • Step c) 1-(p-tolyl)-4-(trifluoromethoxy)pyrazole
  • a solution of a mixture of 3,5-dibrom romethoxy)pyrazole (1550.0 mg, 3.88 mmol, 1.0 eq) and 5-bromo-1-(p-tolyl)-4-(trifluoromethoxy)pyrazole (600.0 mg, 1.87 mmol, 0.48 eq) in MeOH (5 mL) was added to a suspension of Pd/C (500.0 mg, 18.69 mmol, 4.82 eq) in MeOH (5 mL) under an atmosphere of nitrogen.
  • the reaction mixture was degassed an charged with hydrogen for three times and then the mixture was stirred at 25°C for 1 h under an atmosphere of hydrogen.
  • Step b) [2-fluoro-4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methanol
  • methyl 2-fluoro-4-[4 ol-1-yl]benzoate 3400.0 mg, 11.8 mmol, 1.0 eq
  • diisobutylaluminium hydride 50.0 mL, 50.0 mmol, 4.24 eq
  • the reaction mixture was poured into water (100 mL) and the resulting mixture was extracted with EtOAc (300 mL).
  • Step c) 1-[4-(chloromethyl)-3-fluoro-phenyl]-4-(trifluoromet le compound was prepared in ol-1-yl]phenyl]methanol and was obta Fhyl)pyrazole The tit F 3, step b from [2-fluoro-4-[4- (trifluoromethyl)pyraz C Nined as brown oil.
  • Step b) [2-fluoro-6-[4-(trifluoromethyl)pyrazol-1-yl]-3-pyridyl]methanol
  • the title compound was prepared in 11, step b from methyl 2-fluoro-6-[4- (trifluoromethyl)pyrazol-1-yl]pyridine-3-carboxylate and was obtained as light yellow solid.
  • Step c) 3-(chloromethyl)-2-fluoro-6-[4-(trifluoromethyl)pyrazol-1-yl]pyridine The title compound was prepared in a F N F F F 3, step b from [2-fluoro- romethyl)pyrazol-1-yl]-3-pyridy Cl]methanol a Nnd N 6-[4- (trifluo l was obtained as light yellow solid. MS (ESI): 280.1 [M+H] + .
  • Step b) 6-[4-(trifluoromethyl)pyrazol-1-yl]-3-pyridyl]methanol The title compound was prepared in 11, step b from methyl 6-[4- (trifluoromethyl)pyrazol-1-yl]pyridine-3-carboxylate and was obtained as yellow solid. MS (ESI): 244.3 [M+H] + .
  • Step c) 5-(chloromethyl)-2-[4-(trifluoromethyl)p compound was prepared in Cl Nyraz No Nl-1-y Fl]p Fyridine The title F 3, step b from 6-[4- (trifluoromethyl)pyrazol-1-yl]-3-pyridyl]methanol and was obtained as yellow oil.
  • Step b) [3-fluoro-4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methanol
  • the title compound was prepared in 11, step b from methyl 3-fluoro-4-[4- (trifluoromethyl)pyrazol-1-yl]benzoate and was obtained as white solid.
  • Step c) 1-[4-(chloromethyl)-2-fluoro-phenyl]-4-(trifluoromethyl)pyraz e title compound was prepared in a ol-1-yl]phenyl]methanol and was ob Fole Th Fta F F 3, step b from [3-fluoro-4-[4- (trifluoromethyl)pyraz Cl N Nined as light yellow solid. MS (ESI): 279.0 [M+H] + .
  • Step b) 5,5-difluoro-1-(2-methoxyethyl)piperidine-3-carboxylic acid
  • a solution of methyl 5,5-difluoro-1-( yl)piperidine-3-carboxylate (500.0 mg, 2.11 mmol, 1.0 eq) in THF (10 mL) was added a solution of LiOH-H2O (168.61 mg, 4.22 mmol, 2.0 eq) in water (2 mL) drop wise and the reaction mixture was stirred at 20°C for 2 h.
  • the reaction mixture was poured into water (10 mL) and the pH of the mixture was adjusted to 5 by addition of HCl (1M).
  • Step c) 2-amino-4-(2-amino-4-bromo-5-fluoro-phenyl)-4-oxo-butanoic acid A solution of diethyl 2-acetamido-2-[ -fluoro-phenyl)-2-oxo- ethyl]propanedioate (1.95 g, 4.36 mmol, 1 eq) in hydrochloric acid (0.218 M, 20.0 mL, 4.36 mmol, 1 eq) was stirred at 110 °C for 16 h. The mixture was concentrated under vacuum to obtain a brown solid (1.33 g) which was dissolved in water.
  • Step d) 4-(2-amino-4-bromo-5-fluoro-phenyl)-2-(tert-butoxycarbonylamino)-4-oxo-butanoic acid
  • 2-amino-4-(2-amin yl)-4-oxo-butanoic acid (1.33 g, 4.36 mmol, 1 eq)
  • di-t-butyldicarbonate (1.14 g, 5.23 mmol, 1.2 eq)
  • TEA 1.21 mL, 8.72 mmol, 2 eq
  • K2CO3 7.0676 mg, 5.11 mmol, 2.2 eq
  • 4-(trifluoromethoxy)benzyl bromide (0.37 mL, 2.32 mmol, 1 eq) at 0°C and the reaction mixture was then stirred for 16 h at 25°C.
  • Step g) tert-butyl N-[8-bromo-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4- dihydro-1-benzazepin-3-yl]carbamate
  • tert-butyl N-[8-bromo-7-fluoro- , ethoxy)phenyl]methyl]-3,4-dihydro- 1-benzazepin-3-yl]carbamate (2.0 g, 2.85 mmol, 1 eq) was added dropwise DAST (20.0 mL) at 0- 10°C under an atmosphere of nitrogen and the mixture was stirred at 25°C for 12 h.
  • Step j) tert-butyl N-[5,5,7-trifluoro-8-(hydrazinecarbonyl)-2-oxo-1-[[4- (trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate
  • 3-(tert-butoxyc , , oxo-1-[[4- (trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine-8-carboxylic acid 430.0 mg, 0.780 mmol, 1 eq
  • T3P (748.41 mg, 1.18 mmol, 1.5 eq) in DCM (10 mL) were added DIPEA (0.41 mL, 2.35 mmol, 3 eq) and hydrazine monohydrate (0.16 mL, 3.14 mmol, 4 eq) and the reaction mixture was stirred at 20°C for 16 h.
  • Step k) tert-butyl N-[8-[(2,2-dimethylpropanoylamino)carbamoyl]-5,5,7-trifluoro-2-oxo-1-[[4- (trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate
  • DIPEA 0.07 mL, 0.370 mmol, 3 eq
  • HATU 56.79 mg, 0.150 mmol, 1.2 eq
  • pivalic acid 13.98 mg, 0.140 mmol, 1.1 eq
  • Step l tert-butyl N-[8-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5,5,7-trifluoro-2-oxo-1-[[4- (trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate
  • tert-butyl N-[8- , rbamoyl]-5,5,7-trifluoro-2-oxo-1- [[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate 30.0 mg, 0.050 mmol, 1 eq) in toluene (40 mL) was added Burgess Reagent (44.23 mg, 0.190 mmol, 4 eq) at 25°C and the reaction mixture was heated to 100°C for 16 h.
  • tert-butyl N-[5,5,7-trifluoro-8-(hydrazinecarbonyl)-2- oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate (Example 1, step j) (170.0 mg, 0.3 mmol, 1.0 eq) was added at 15°C and the reaction mixture was stirred at 20°C for 16 h. The reaction mixture was concentrateed under vacuum to remove THF, then it was diluted with EtOAc (20 mL), washed with H2O (10 mL), brine (10 mL x 3) and dried over anhydrous Na2SO4.
  • Step b) tert-butyl N-[8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1- [[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamte
  • the title compound was prepa , rom tert-butyl N-[8-[[(2-cyano-2- methyl-propanoyl)amino]carbamoyl]-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]- 3,4-dihydro
  • Step b) tert-butyl N-[5,5,7-trifluoro-8-(5-morpholino-1,3,4-oxadiazol-2-yl)-2-oxo-1-[[4- (trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate
  • the title compound was prep , om tert-butyl N-[5,5,7-trifluoro- 8-[(morpholine-4-carbonylamino)carbamoyl]-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4- dihydro-1-benzazepin-3-yl]carbamate (280.0 mg, 0.41 mmol) and was obtained as yellow oil (120.0 mg, 0.18 mmol, 44% yield).
  • HATU 64.99 mg, 0.171 mmol, 1.5 eq
  • the solution was concentrated to give a light yellow foam which was dissolved in THF (0.940 mL) and Burgess Reagent (135.78 mg, 0.570 mmol, 5 eq) was added in one portion and the mixture was stirred for 1 h.
  • the mixture was diluted with EtOAc and water and extracted with EtOAc.
  • Step d) tert-butyl N-[5,5,7-trifluoro-8-(hydrazinecarbonyl)-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4- dihydro-1-benzazepin-3-yl]carbamate
  • the title compound was prepare j from 3-(tert- butoxycarbonylamino)-5,5,7-trifluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1- benzazepine-8-carboxylic acid (150.0 mg, 0.27 mmol, 1.0 eq) and was obtained as light yellow solid (120 mg, 0.180 mmol, 69% yield).
  • Chiral SFC retention time 2.32 minutes (column: Chiralcel OD-350 ⁇ 4.6 mm I.D., 3 ⁇ m; mobile phase: phase A for CO2, and phase B for MeOH (0.05% DEA); gradient elution: MeOH (0.05% DEA) in CO 2 from 5% to 40%; flow rate: 3 mL/min; detector: DAD; column temperatur: 35°C; back pressure: 100 bar).
  • the title compound was prepared in a step b from 1-(2-amino-4-bromo- phenyl)-2-chloro-ethanone (9.28 g) and was obtained as green oil (8.7 g).
  • Step c) 2-amino-4-(2-amino-4-bromo-phenyl)-4-oxo-butanoic acid A solution of diethyl 2-acetamido-2-[ henyl)-2-oxo-ethyl]propanedioate (5.5 g, 12.81 mmol, 1.0 eq) in HCl (12 M, 60.0 mL, 720.0 mmol, 56.19 eq) was stirred at 100°C for 12 h. The reaction mixture was concentrated under vacuum to give the title compound as hydrochloride salt (3.7 g) as green oil which was used in the next reaction step without further purification. MS (ESI): 289.0 [M+H] + .
  • Step d) 4-(2-amino-4-bromo-phenyl)-2-(tert-butoxycarbonylamino)-4-oxo-butanoic acid
  • the title compound was prepared in , ep d from 2-amino-4-(2-amino-4- bromo-phenyl)-4-oxo-butanoic acid (2.0 g, 6.97 mmol, 1.0 eq) and was obtained as light yellow oil (2.51 g, 6.48 mmol, 93% yield).
  • Step e tert-butyl N-(8-bromo-2,5-dioxo-3,4-dihydro-1H-1-benzazepin-3-yl)carbamate
  • the title compound was prepared in analogy to Example 1, step e from 4-(2-amino-4-bromo- phenyl)-2-(tert-butoxycarbonylamino)-4-oxo-butanoic acid (2.6 g, 6.71 mmol, 1.0 eq) and was obtained as light yellow solid (800.0 mg, 2.17 mmol, 29% yield).
  • the title compound was prepared i r N O Oep f from tert-butyl N-(8-bromo-2,5- dioxo-3,4-dihydro-1H-1-benzazepin-3-yl)carbamate (650 mg, 1.76 mmol, 1.0 eq) and 1- (chloromethyl)-4-phenoxy-benzene (385 mg, 1.76 mmol, 1.0 eq) and was obtained as light yellow solid (350.0 mg, 0.635 mmol, 36% yield).
  • Step i) tert-butyl N-[5,5-difluoro-8-(hydrazinecarbonyl)-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4- dihydro-1-benzazepin-3-yl]carbamate
  • the title compound was prepare j from 3-(tert- butoxycarbonylamino)-5,5-difluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1- benzazepine-8-carboxylic acid (270.0 mg, 0.5 mmol, 1.0 eq). A light yellow solid (260.0 mg) was obtained which was used in the next reaction step without further purification.
  • Step j) tert-butyl N-[5,5-difluoro-8-[[(2-methyl-2-methylsulfonyl-propanoyl)amino]carbamoyl]-2- oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate
  • the title compound was prep om tert-butyl N-[5,5-difluoro-8- (hydrazinecarbonyl)-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate (260.0 mg, 0.47 mmol, 1.0 eq) and 2-methyl-2-methylsulfonyl-propanoic acid (93.84 mg, 0.56 mmol, 1.2 eq).
  • Chiral SFC retention time 2.43 minutes (column: Chiralcel OD-350 ⁇ 4.6 mm I.D., 3 ⁇ m; mobile phase: phase A for CO2, and phase B for MeOH (0.05% DEA); gradient elution: MeOH (0.05% DEA) in CO2 from 5% to 40%; flow rate: 3 mL/min; detector: PDA; column temperatur: 35°C; back pressure: 100 bar).
  • Step b) tert-butyl N-[(3S)-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2- yl]-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3- yl]carbamate and tert-butyl N-[(3R)-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4- oxadiazol-2-yl]-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1- benzazepin-3-
  • tert-butyl N , , , , -yl]-2-oxo-1- [[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate (95 mg) was subjected to preparative SFC (Daicel Chiralpak IC (250 mm x 30 mm,10 ⁇ m), 0.1% NH3- H2O in IPA) to obtain tert-butyl N-[5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4- oxadiazol-2-yl]-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1- benzazepin-3-yl]carbamate [isomer B] (28
  • tert-butyl N 4-(4- methoxyphenyl)phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepin-3-yl]carbamate (80 mg) was subjected to preparative SFC (Daicel Chiralpak AD (250 mm x 30 mm,10 ⁇ m), 0.1% NH3-H2O in IPA) to obtain tert-butyl N-[8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1- [[4-(4-methoxyphenyl)phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepin-3-yl]carbamate [isomer B] (38 mg) (MS (ESI): 606.2 [M-isobutene+H] + , retention time 2.22 minutes (see conditions below) as yellow solid and ter
  • Step b) tert-butyl N-[(3S)-8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo- 1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate and tert-butyl N-[(3R)-8- [5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[(4- phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate tert-butyl N-[ oxo-1-[(4- phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate tert
  • Example 12 2-methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-2- pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile and 2-methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-2- pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile Step a) tert-b , , , , uoro-2-oxo-1- [[4-[5-(trifluoromethyl)-2-pyridyl]phen
  • hydrazine monohydrochloride (127.0 mg, 1.53 mmol, 3.0 eq) and DIPEA (0.27 mL, 1.53 mmol, 3.0 eq) were added at 20°C and the mixture was stirred at 20°C for 0.5 h and then poured into water. The mixture was extracted with DCM (3 x 20 mL) and the combined extracts were washed with brine (50 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum.
  • Step b) tert-butyl N-[(3S)-5,5,7-trifluoro-2-oxo-8-(5-pyrrolidin-1-yl-1,3,4-oxadiazol-2-yl)-1-[[4-[5- (trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate and tert-butyl N-[(3R)-5,5,7-trifluoro-2-oxo-8-(5-pyrrolidin-1-yl-1,3,4-oxadiazol-2-yl)-1-[[4-[5- (trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate tert-butyl
  • Step b) tert-butyl N-[(3S)-5,5,7-trifluoro-8-[5-(4-oxa-7-azaspiro[2.5]octan-7-yl)-1,3,4-oxadiazol-2- yl]-2-oxo-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepin- 3-yl]carbamate and tert-butyl N-[(3R)-5,5,7-trifluoro-8-[5-(4-oxa-7-azaspiro[2.5]octan-7-yl)-1,3,4- oxadiazol-2-yl]-2-oxo-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phen
  • the pH of the reaction mixture was adjusted to 8 by careful addition of saturated NaHCO 3 solution and the resulting mixture was extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (5 mL), dried (Na2SO4) and concentrated. The remaining residue was dissolved in EtOAc (20 mL) and HCl/EtOAc (4M, 0.2 mL) was added.
  • reaction mixture was poured into water (20 mL), the layers were separated and the aqueous phase was extracted with EtOAc (10 mL x 3). The combined organic phases were washed with brine (20 mL), dried (Na 2 SO 4 ) and concentrated.
  • Step b) tert-butyl N-[(3S)-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2- yl]-2-oxo-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3- yl]carbamate and tert-butyl N-[(3R)-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4- oxadiazol-2-yl]-2-oxo-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-di
  • Step b) tert-butyl N-[(3S)-8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo- 1-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate and tert-butyl N-[(3R)-8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1- [[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate
  • Step b) tert-butyl N-[(3S)-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2- yl]-2-oxo-1-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3- yl]carbamate and tert-butyl N-[(3R)-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4- oxadiazol-2-yl]-2-oxo-1-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3- yl]carbamate and tert-buty
  • the pH of the reaction mixture was adjusted to 8 by careful addition of saturated NaHCO3 solution.
  • the resulting mixture was extracted with DCM (10 mL x 3) and the combined organic layers were washed with brine (10 mL), dried (Na2SO4) and concentrated. The remaining residue was dissolved in EtOAc (20 mL) and HCl/EtOAc (4M, 0.2 mL) was added.
  • the title compound was prepared in analogy to Example 1, steps a to l (using 1-[4- (chloromethyl)phenyl]-4-(trifluoromethyl)pyrazole [CAS# 1486714-19-5] instead of 4- (trifluoromethoxy)benzyl bromide in step f and 2-methyl-2-methylsulfonyl-propanoic acid instead of pivalic acid in step k) and was obtained as yellow oil.
  • reaction mixture was poured into water (10 mL) and the resulting mixture was extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (5 mL), dried (Na2SO4) and concentrated. The remaining residue was dissolved in EtOAc (20 mL) and HCl/EtOAc (4M, 0.2 mL) was added.
  • Step c) methyl 1-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-2- pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-3- azabicyclo[3.1.1]heptane-3-carboxylate and methyl 1-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4- [5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2- yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate To a solution of 3-amino-8-[5-(3-azabicy
  • Example 36 methyl 1-[5-[(3S)-3-amino-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1- benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate and methyl 1-[5-[(3R)-3-amino-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1- benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate Step a) tert-butyl 1-[5-[3-(tert-butoxycarbonylamino)-1-[(4-chlorophenyl)methyl]-5,5,7-trifluor
  • Step c) methyl 1-[5-[3-amino-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1- benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate
  • dihydrochloride (106.0 mg, 0.18 mmol, 1.0 eq) and DIPEA (0.16 mL, 0.9 mmol, 5.0 eq) in DCM (10 mL) was added dimethyl dicarbonate (0.01 mL, 0.09
  • Step d) methyl 1-[5-[(3S)-3-amino-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1- benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate and methyl 1-[5- [(3R)-3-amino-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepin-8-yl]- 1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate methyl 1-[5-[3-amino-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benz
  • the title compound was prepared in analogy to Example 1, steps a to l (using 2-[4- (chloromethyl)phenyl]-5-(1,1-difluoroethyl)pyridine (Intermediate 7) instead of 4- (trifluoromethoxy)benzyl bromide in step f and 2-cyano-2-methyl-propanoic acid instead of pivalic acid in step k) and was obtained as solid.
  • Step b) tert-butyl N-[(3S)-8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(1,1- difluoroethyl)-2-pyridyl]phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepin-3- yl]carbamate and tert-butyl N-[(3R)-8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5- (1,1-difluoroethyl)-2-pyridyl]phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepin
  • Step a) tert-butyl N-[8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-(5- methoxy-2-pyridyl)phenyl]methyl]-2-oxo-3,4-dihyd pared in analogy to Ex id in step k) and was obtained as solid.
  • Step b) tert-butyl N-[(3S)-5,5,7-trifluoro-1-[[4-(5-methoxy-2-pyridyl)phenyl]methyl]-8-[5-(1- methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-3,4-dihydro-1-benzazepin-3- yl]carbamate and tert-butyl N-[(3R)-5,5,7-trifluoro-1-[[4-(5-methoxy-2-pyridyl)phenyl]methyl]-8- [5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-3,4-dihydro-1-benzazepin-3- yl]carbamate ter
  • Step b) tert-butyl N-[(3S)-8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5- (difluoromethyl)-2-pyridyl]phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepin-3- yl]carbamate and tert-butyl N-[(3R)-8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5- (difluoromethyl)-2-pyridyl]phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepin-3- yl]carbamate tert
  • Step b) tert-butyl N-[(3S)-8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5- (difluoromethoxy)-2-pyridyl]phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepin-3- yl]carbamate and tert-butyl N-[(3R)-8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5- (difluoromethoxy)-2-pyridyl]phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepin-3- yl]carbamate and tert-butyl N-[(3R)-8-
  • Step b) tert-butyl N-[(3S)-8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[2- fluoro-6-[4-(trifluoromethyl)pyrazol-1-yl]-3-pyridyl]methyl]-2-oxo-3,4-dihydro-1-benzazepin-3- yl]carbamate and tert-butyl N-[(3R)-8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7- trifluoro-1-[[2-fluoro-6-[4-(trifluoromethyl)pyrazol-1-yl]-3-pyridyl]methyl]-2-oxo-3,4-dihydro-1-
  • Step b) tert-butyl N-[(3S)-8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[3- fluoro-4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepin-3- yl]carbamate and tert-butyl N-[(3R)-8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7- trifluoro-1-[[3-fluoro-4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-2-oxo-3,4-dihydro-1- benzazepin-3-yl]carbamate and tert-butyl N-[
  • the mixture was diluted with DCM (1.5 mL) and the pH of the mixture was adjusted to 8 by careful addition of saturated NaHCO3 solution.
  • the resulting mixture was extracted with DCM (3 mL x 3) and the the organic extracts were washed with brine (7 mL), dried (Na2SO4) and concentrated. The remaining residue was dissolved in EtOAc (10 mL) and HCl/EtOAc (4 M, 0.3 mL) was added.
  • DGK ⁇ and ⁇ kinase use ATP to phosphorylate the substrate 1,2-dilauroyl-sn-glycerol (DLG, incorporated in the liposomes). ATP is converted to ADP as a result of this enzymatic reaction. After the kinase reaction, an ATP-depletion reagent is added to terminate the kinase reaction and deplete any remaining ATP, leaving only ADP. Second, a detection reagent is added to simultaneously convert ADP to ATP and allow the newly synthesized ATP to be converted to light using a coupled luciferase/luciferin reaction.
  • DDGK ⁇ and ⁇ kinase use ATP to phosphorylate the substrate 1,2-dilauroyl-sn-glycerol (DLG, incorporated in the liposomes). ATP is converted to ADP as a result of this enzymatic reaction. After the kinase reaction, an ATP-depletion reagent is added
  • Reagents and Material Buffer Ingredients Chemicals Vendor Cat. Nr.: Protein / Substrates / Tracer Proteins / Substrate / Tracer Vendor Lot#; Probe# 16:0-18:1 PC Sigma - Aldrich Cat# 850457C Full length DGKA and Z were expressed in Sf21 insect cells by infecting the cells with the baculovirus stock at MOI of 2. Purification of both enzymes was performed as previously described by Takahashi et al., PeerJ, 2018 (Takahashi, D.; Sakane, F. Expression and purification of human diacylglycerol kinase alpha from baculovirus-infected insect cells for structural studies.
  • the reactions were started by addition of DGK ⁇ and ⁇ kinases at 4 nM and 2 nM final concentrations, respectively. After 1 hour reaction, the amount of ADP formed was detected with the ADP-Glo kinase assay (Promega) according to the manufacturer instructions. Compounds were added in 11-points dose response, starting at 10 mM, 1:3 dilutions, with a final DMSO concentration of 2%. The multidrop combi was used as a liquid handler and luminescence was read with 0.5 s by the envision reader (PE).
  • PE envision reader
  • a detection reagent is added to simultaneously convert ADP to ATP and allow the newly synthesized ATP to be converted to light using a coupled luciferase/luciferin reaction.
  • Experimental Procedure Reagents and Material DGK ⁇ and ⁇ kinase ADP Glo assays were ran by Reaction Biology Corp., 1 Great Valley Parkway, Suite 2, Malvern, 19355, PA, USA. Information provided by the service provider are the following: DGK ⁇ and ⁇ kinases were used at 2 nM final concentration. Reactions were carried out at 50 ⁇ M ATP.500 uM of the substrate DLG (Dilauroyl-sn-glycerol) was used.
  • PBS++ with PBS-- or PBS++ with CD3 antibody concentration depending on donor and determined by CD3 titrations
  • CD3 antibody concentration depending on donor and determined by CD3 titrations
  • Cells were then seeded 80 ⁇ l/well to the 40 ⁇ l/well including dispensed compounds according to plate layout. By adding cells, compounds were further diluted 1:3, and resulting in 100k cells/120 ⁇ l/well. After 24 hours 40 ⁇ l of supernatant was collected carefully from the top while not disturbing the cells and transferred into a round bottom 96well plate. Collected and frozen supernatant was used for detection of IL2 using the IL-2 Human ProQuantum Immunoassay Kit (Invitrogen) or using the Human IL-2 ELISA Kit (Thermo Fisher).
  • Compound treatment Compounds were added in a 5 or 6pt dose response with the Tecan D300e Digital Dispenser, all conditions 3 times more concentrated than the end-concentration, since cells are added afterwards (80 ⁇ l cells to 40 ⁇ l prepared medium with treatment).
  • the DR was starting at 20 ⁇ M or 10 ⁇ M final top concentration and a dilution factor of 3.333.
  • the positive control was the reference compound A1 that was added in a dose response as well, additionally to 3 wells of only 20 ⁇ M representing the positive stimulator control. All wells were normalized with DMSO to a final concentration of 0.6% (0.2% end-concentration).
  • IL2 ProQuantum Immunoassay The immunoassay is done following the manufacturer’s manual (Invitrogen, #A35603). Additional information: For the immunoassay, MicroAmpTM EnduraPlateTM Optical 384-Well plates are used. Frozen supernatant is thawed and centrifuged for 5 minutes at 1000xg, both steps at 4°C. After centrifugation, required sample amount is taken from the top, and in a separate LightCycler V- bottom plate (working plate) diluted with assay dilution buffer, dilution factor depending on the PBS or CD3 condition but at least 1:3.
  • IL-2 standard and blanks are prepared in the same V-bottom plate, standard with a range of 0.0128-5000 pg/ml (extended version). After preparation, 5 ⁇ l of sample dilutions or standard/blanks are transferred to the optical 384-well plate (assay plate) and the 10 ⁇ l reaction protocol is being followed. For measurement, the QuantStudio 12K Flex system is used. Raw data is extracted and IL-2 concentrations are calculated with the Thermo Fisher online app (apps.thermofisher.com/apps/proquantum). IL2 Elisa ELISA is done following the manufacturer’s manual (Thermo Fisher Scientific, #88-7025-88).
  • ELISA Nunc MaxiSorp 96well plates are used. Frozen supernatant is thawed and centrifuged for 5 minutes at 1000xg, both steps at 4°C. After that, required sample amount is taken from the top, and in a separate V-bottom plate diluted with ELISA diluent, dilution factor depending on the PBS or CD3 condition. IL-2 standard and blanks are prepared in the same V-bottom plate. After preparation, 50 ⁇ l of sample dilutions and 100 ⁇ l of standard or blanks are transferred to the Nunc plates.
  • PBS++ only or PBS++ with CD3 antibody (concentration depending on donor and determined by CD3 titrations) is added 100 ⁇ l/well to Poly-D Lysine coated 96-well plates. Plates are sealed and incubated at room temperature for 3 hours on a table-top rocking platform. After incubation, plates are washed once with PBS-- and filled with 40 ⁇ l/well culture medium only. Compounds are then added (see next section) to medium only plates. After 3 hours of culturing the T-cells, cells are filtered through a cell strainer (Miltenyi Biotech, #130-041-407), counted again and concentration is adjusted to 1.25 Mio/ml.
  • a cell strainer Miltenyi Biotech, #130-041-407
  • Cells are then seeded 80 ⁇ l/well to the 40 ⁇ l/well including dispensed compounds according to plate layout. By adding cells, compounds are further diluted 1:3, and resulting in 100k cells/120 ⁇ l/well. After 48 hours 40 ⁇ l of supernatant is collected carefully from the top while not disturbing the cells. Cells are assessed for proliferation 5 days later by measuring ATP consumption using CellTiterGlo (Promega). Compound treatment Compounds were added in a 5 or 6pt dose response with the Tecan D300e Digital Dispenser, all conditions 3 times more concentrated than the end-concentration, since cells are added afterwards (80 ⁇ l cells to 40 ⁇ l prepared medium with treatment).
  • the DR was starting at 20 ⁇ M or 10 ⁇ M final top concentration and a dilution factor of 3.333.
  • the positive control was the reference compound A1 that was added in a dose response as well, additionally to 3 wells of only 20 ⁇ M representing the positive stimulator control. All wells were normalized with DMSO to a final concentration of 0.6% (0.2% end-concentration).
  • Cell Titer Glo Measurements After 5 days, for detection of ATP which is directly proportional to the number of cells present per well, the CellTiter-Glo® 2.0 Reagent is used. After visual control for toxicity or precipitations of the tested compounds, the plates are equilibrated to room temperature for 45 minutes. CellTiter-Glo® 2.0 Reagent is equilibrated to room temperature as well.
  • MV-3 RFP cells are cultured in MV-3 medium (DMEM + 10% FBS, 1x PenStrep and 0.5 ⁇ g/mL Puromycin) for at least 3 weeks. Cultured MV-3 cells at 80% confluency are washed once with PBS-- and trypsinized until detached.
  • T-cell medium RPMI 1640 + 5% human serum + 1mM Sodium Pyruvate + 50 ⁇ M 2- mercaptoethanol and 1x Pen-Strep.
  • Cells are seeded with 100 ⁇ L/well into a 96-well plate (TTP, #92696), and placed for 40 minutes without moving at room temperature in order to achieve evenly distributed attachment of cells. Plates are then incubated until further use.
  • expanded primary human T-cells are thawed and resuspended in T-cell medium to 4*106 cells/mL. For 3 hours, they are cultured in a 6-well plate with 6 mL per well at maximum.
  • T-cells After culturing the T-cells, they are filtered through a cell strainer (Miltenyi Biotech, #130-041- 407), counted again, and cell concentration is adjusted to 2*106 cells/mL.
  • Compound treatment MCSP-TCB or PBS are pre-diluted in T-cell medium (concentration depending on T-cell donor), 4 times more concentrated than the end-concentration.60 ⁇ L/well of pre-dilutions are then distributed into a round bottom plate (Costar, #3799) according to plate layout. Compounds are added in a 9pt dose response with the Tecan D300e Digital Dispenser, as well 4 times more concentrated than the end-concentration.
  • DMSO concentration of all wells is adjusted to 0.8 %, resulting in 0.2 % as final concentration.
  • 60 ⁇ L per well of T-cell suspension are added to the prepared round bottom plate and resuspended with a manual multichannel.100 ⁇ L/well of the resuspended T-cell suspension including treatments are then transferred cautiously to the over-night cultured MV-3 cells according to plate layout.100 ⁇ L T-cell medium only is added to the outer MV-3 wells only.
  • Final compound DR is starting at 20 ⁇ M with a dilution factor of 3.333.
  • Final TCB concentration is between 1.5 pM to 5 pM and was determined for each T-cell donor individually by running TCB titrations.
  • TCB concentration For each donor, a TCB concentration was chosen which corresponds to 10-20% of MV3 baseline cell killing in the absence of compound treatment.
  • Positive control is the reference compound A1 which is added in a DR, as well as additional wells with only 20 ⁇ M.20 ⁇ M of reference compound A1 represent the positive stimulator control, TCB only (DMSO wells) the neutral control.
  • TCB only DMSO wells

Abstract

La présente invention concerne de nouveaux dérivés bicycliques de tétrahydroazépine de formule générale (I) dans laquelle R1, R2 et R4 sont tels que définis dans la description, des compositions contenant les composés, des procédés de fabrication des composés et des procédés d'utilisation des composés.
PCT/EP2023/072129 2022-08-11 2023-08-10 Dérivés bicycliques de tétrahydroazépine WO2024033458A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP22189830 2022-08-11
EP22189830.7 2022-08-11

Publications (1)

Publication Number Publication Date
WO2024033458A1 true WO2024033458A1 (fr) 2024-02-15

Family

ID=82898753

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2023/072129 WO2024033458A1 (fr) 2022-08-11 2023-08-10 Dérivés bicycliques de tétrahydroazépine

Country Status (1)

Country Link
WO (1) WO2024033458A1 (fr)

Citations (55)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4943533A (en) 1984-03-01 1990-07-24 The Regents Of The University Of California Hybrid cell lines that produce monoclonal antibodies to epidermal growth factor receptor
US5212290A (en) 1989-09-08 1993-05-18 The Johns Hopkins University Antibodies specific for type II mutant EGTR
EP0659439A2 (fr) 1993-12-24 1995-06-28 MERCK PATENT GmbH Immunoconjugués
US5457105A (en) 1992-01-20 1995-10-10 Zeneca Limited Quinazoline derivatives useful for treatment of neoplastic disease
US5475001A (en) 1993-07-19 1995-12-12 Zeneca Limited Quinazoline derivatives
WO1996003397A1 (fr) 1994-07-21 1996-02-08 Akzo Nobel N.V. Formulations de peroxides cetoniques cycliques
WO1996030347A1 (fr) 1995-03-30 1996-10-03 Pfizer Inc. Derives de quinazoline
WO1996033980A1 (fr) 1995-04-27 1996-10-31 Zeneca Limited Derives de quinazoline
WO1996033978A1 (fr) 1995-04-27 1996-10-31 Zeneca Limited Derives de quinazoline
WO1996040210A1 (fr) 1995-06-07 1996-12-19 Imclone Systems Incorporated Anticorps et fragments d'anticorps inhibant la croissance des tumeurs
US5654307A (en) 1994-01-25 1997-08-05 Warner-Lambert Company Bicyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family
WO1997038983A1 (fr) 1996-04-12 1997-10-23 Warner-Lambert Company Inhibiteurs irreversibles de tyrosine kinases
WO1998014451A1 (fr) 1996-10-02 1998-04-09 Novartis Ag Derive de pyrazole condense et procede pour sa preparation
US5747498A (en) 1996-05-28 1998-05-05 Pfizer Inc. Alkynyl and azido-substituted 4-anilinoquinazolines
US5760041A (en) 1996-02-05 1998-06-02 American Cyanamid Company 4-aminoquinazoline EGFR Inhibitors
US5804396A (en) 1994-10-12 1998-09-08 Sugen, Inc. Assay for agents active in proliferative disorders
WO1998043960A1 (fr) 1997-04-03 1998-10-08 American Cyanamid Company 3-cyano quinolines substituees
WO1998050038A1 (fr) 1997-05-06 1998-11-12 American Cyanamid Company Utilisation de composes de la quinazoline dans le traitement de la maladie polykystique des reins
WO1998050433A2 (fr) 1997-05-05 1998-11-12 Abgenix, Inc. Anticorps monoclonaux humains contre le recepteur du facteur de croissance epidermique
US5866572A (en) 1996-02-14 1999-02-02 Zeneca Limited Quinazoline derivatives
WO1999006396A1 (fr) 1997-07-29 1999-02-11 Warner-Lambert Company Inhibiteurs bicycliques irreversibles de tyrosine kinases
WO1999006378A1 (fr) 1997-07-29 1999-02-11 Warner-Lambert Company Inhibiteurs irreversibles de tyrosines kinases
WO1999009016A1 (fr) 1997-08-01 1999-02-25 American Cyanamid Company Derives de quinazoline substitues et leur utilisation en tant qu'inhibiteurs de la tyrosine kinase
US5891996A (en) 1972-09-17 1999-04-06 Centro De Inmunologia Molecular Humanized and chimeric monoclonal antibodies that recognize epidermal growth factor receptor (EGF-R); diagnostic and therapeutic use
WO1999024037A1 (fr) 1997-11-06 1999-05-20 American Cyanamid Company Traitement des polypes du colon par des inhibiteurs de la tyrosine kinase a base de derives de quinazoline
US6002008A (en) 1997-04-03 1999-12-14 American Cyanamid Company Substituted 3-cyano quinolines
US6084095A (en) 1994-01-25 2000-07-04 Warner-Lambert Company Substituted pyrido[3,2-d]pyrimidines capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family
US6140332A (en) 1995-07-06 2000-10-31 Novartis Ag Pyrrolopyrimidines and processes for the preparation thereof
US6344455B1 (en) 1998-11-19 2002-02-05 Warner-Lambert Company N-[4-(3-chloro-4-fluoro-phenylamino)-7-(3-morpholin-4-yl-propoxy)-quinazolin-6-yl]-acrylamide, and irreversible inhibitor of tyrosine kinases
US6391874B1 (en) 1996-07-13 2002-05-21 Smithkline Beecham Corporation Fused heterocyclic compounds as protein tyrosine kinase inhibitors
US6596726B1 (en) 1994-01-25 2003-07-22 Warner Lambert Company Tricyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family
WO2006029879A2 (fr) 2004-09-17 2006-03-23 F.Hoffmann-La Roche Ag Anticorps anti-ox40l
WO2006105021A2 (fr) 2005-03-25 2006-10-05 Tolerrx, Inc. Molecules de liaison gitr et leurs utilisations
WO2006122150A1 (fr) 2005-05-10 2006-11-16 Incyte Corporation Modulateurs de l'indolamine 2,3-dioxygenase et leurs procedes d'utilisation
WO2007005874A2 (fr) 2005-07-01 2007-01-11 Medarex, Inc. Anticorps monoclonaux humains diriges contre un ligand de mort programmee de type 1(pd-l1)
WO2007075598A2 (fr) 2005-12-20 2007-07-05 Incyte Corporation N-hydroxyamidinoheterocycles en tant que modulateurs d'indoleamine 2,3-dioxygenase
WO2008036642A2 (fr) 2006-09-19 2008-03-27 Incyte Corporation N-hydroxyamidinohétérocycles en tant que modulateurs d'indoléamine 2,3-dioxygénase
WO2008036653A2 (fr) 2006-09-19 2008-03-27 Incyte Corporation N-hydroxyamidinohétérocycles modulateurs de l'indoléamine 2,3-dioxygénase
WO2008132601A1 (fr) 2007-04-30 2008-11-06 Immutep Anticorps monoclonal anti-lag-3 cytotoxique et son utilisation dans le traitement ou la prévention d'un rejet du greffon d'organe et de maladies auto-immunes
WO2009009116A2 (fr) 2007-07-12 2009-01-15 Tolerx, Inc. Thérapies combinées utilisant des molécules de liaison au gitr
WO2009044273A2 (fr) 2007-10-05 2009-04-09 Immutep Utilisation d'une protéine lag-3 recombinée ou de dérivés de celle-ci pour produire une réponse immunitaire des monocytes
WO2009073620A2 (fr) 2007-11-30 2009-06-11 Newlink Genetics Inhibiteurs de l'ido
WO2009115652A2 (fr) 2008-01-03 2009-09-24 Universite De La Mediterannee, Aix-Marseille Ii Composition et procedes utilisables lors d'un traitement anti-vih
WO2010019570A2 (fr) 2008-08-11 2010-02-18 Medarex, Inc. Anticorps humains qui se lient au gène 3 d'activation des lymphocytes (lag-3), et leurs utilisations
WO2010077634A1 (fr) 2008-12-09 2010-07-08 Genentech, Inc. Anticorps anti-pd-l1 et leur utilisation pour améliorer la fonction des lymphocytes t
WO2011028683A1 (fr) 2009-09-03 2011-03-10 Schering Corporation Anticorps anti-gitr
WO2011056652A1 (fr) 2009-10-28 2011-05-12 Newlink Genetics Dérivés imidazole comme inhibiteurs de l'ido
WO2011109400A2 (fr) 2010-03-04 2011-09-09 Macrogenics,Inc. Anticorps réagissant avec b7-h3, fragments immunologiquement actifs associés et utilisations associées
WO2012032433A1 (fr) 2010-09-09 2012-03-15 Pfizer Inc. Molécules de liaison 4-1bb
WO2012142237A1 (fr) 2011-04-15 2012-10-18 Newlink Geneticks Corporation Dérivés d'imidazole fusionnés pouvant être employés en tant qu'inhibiteurs d'ido
WO2012145493A1 (fr) 2011-04-20 2012-10-26 Amplimmune, Inc. Anticorps et autres molécules qui se lient à b7-h1 et à pd-1
WO2013079174A1 (fr) 2011-11-28 2013-06-06 Merck Patent Gmbh Anticorps anti-pd-l1 et utilisations associées
WO2014008218A1 (fr) 2012-07-02 2014-01-09 Bristol-Myers Squibb Company Optimisation d'anticorps se liant à la protéine lag-3 exprimée par le gène 3 d'activation des lymphocytes, et leurs utilisations
WO2014023708A1 (fr) * 2012-08-09 2014-02-13 F. Hoffmann-La Roche Ag Hétéro-azépinones substituées
WO2016139181A1 (fr) 2015-03-02 2016-09-09 Apeiron Biologics Ag Dérivés tétrahydrothiazépine bicycliques utiles pour le traitement de maladies infectieuses et/ou néoplasiques

Patent Citations (66)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5891996A (en) 1972-09-17 1999-04-06 Centro De Inmunologia Molecular Humanized and chimeric monoclonal antibodies that recognize epidermal growth factor receptor (EGF-R); diagnostic and therapeutic use
US4943533A (en) 1984-03-01 1990-07-24 The Regents Of The University Of California Hybrid cell lines that produce monoclonal antibodies to epidermal growth factor receptor
US5212290A (en) 1989-09-08 1993-05-18 The Johns Hopkins University Antibodies specific for type II mutant EGTR
US5616582A (en) 1992-01-20 1997-04-01 Zeneca Limited Quinazoline derivatives as anti-proliferative agents
US5457105A (en) 1992-01-20 1995-10-10 Zeneca Limited Quinazoline derivatives useful for treatment of neoplastic disease
US5475001A (en) 1993-07-19 1995-12-12 Zeneca Limited Quinazoline derivatives
EP0659439A2 (fr) 1993-12-24 1995-06-28 MERCK PATENT GmbH Immunoconjugués
US6084095A (en) 1994-01-25 2000-07-04 Warner-Lambert Company Substituted pyrido[3,2-d]pyrimidines capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family
US6265410B1 (en) 1994-01-25 2001-07-24 Warner-Lambert Company Bicyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family
US6455534B2 (en) 1994-01-25 2002-09-24 Warner-Lambert Company Bicyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family
US5654307A (en) 1994-01-25 1997-08-05 Warner-Lambert Company Bicyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family
US5679683A (en) 1994-01-25 1997-10-21 Warner-Lambert Company Tricyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family
US6713484B2 (en) 1994-01-25 2004-03-30 Warner-Lambert Company Bicyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family
US6596726B1 (en) 1994-01-25 2003-07-22 Warner Lambert Company Tricyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family
US6521620B1 (en) 1994-01-25 2003-02-18 Warner-Lambert Company Bicyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family
WO1996003397A1 (fr) 1994-07-21 1996-02-08 Akzo Nobel N.V. Formulations de peroxides cetoniques cycliques
US5804396A (en) 1994-10-12 1998-09-08 Sugen, Inc. Assay for agents active in proliferative disorders
WO1996030347A1 (fr) 1995-03-30 1996-10-03 Pfizer Inc. Derives de quinazoline
US5770599A (en) 1995-04-27 1998-06-23 Zeneca Limited Quinazoline derivatives
WO1996033978A1 (fr) 1995-04-27 1996-10-31 Zeneca Limited Derives de quinazoline
WO1996033980A1 (fr) 1995-04-27 1996-10-31 Zeneca Limited Derives de quinazoline
WO1996040210A1 (fr) 1995-06-07 1996-12-19 Imclone Systems Incorporated Anticorps et fragments d'anticorps inhibant la croissance des tumeurs
US6140332A (en) 1995-07-06 2000-10-31 Novartis Ag Pyrrolopyrimidines and processes for the preparation thereof
US5760041A (en) 1996-02-05 1998-06-02 American Cyanamid Company 4-aminoquinazoline EGFR Inhibitors
US6399602B1 (en) 1996-02-14 2002-06-04 Zeneca Limited Quinazoline derivatives
US5866572A (en) 1996-02-14 1999-02-02 Zeneca Limited Quinazoline derivatives
US6344459B1 (en) 1996-04-12 2002-02-05 Warner-Lambert Company Irreversible inhibitors of tyrosine kinases
WO1997038983A1 (fr) 1996-04-12 1997-10-23 Warner-Lambert Company Inhibiteurs irreversibles de tyrosine kinases
US6602863B1 (en) 1996-04-12 2003-08-05 Warner-Lambert Company Irreversible inhibitors of tyrosine kinases
US5747498A (en) 1996-05-28 1998-05-05 Pfizer Inc. Alkynyl and azido-substituted 4-anilinoquinazolines
US6391874B1 (en) 1996-07-13 2002-05-21 Smithkline Beecham Corporation Fused heterocyclic compounds as protein tyrosine kinase inhibitors
WO1998014451A1 (fr) 1996-10-02 1998-04-09 Novartis Ag Derive de pyrazole condense et procede pour sa preparation
WO1998043960A1 (fr) 1997-04-03 1998-10-08 American Cyanamid Company 3-cyano quinolines substituees
US6002008A (en) 1997-04-03 1999-12-14 American Cyanamid Company Substituted 3-cyano quinolines
US6235883B1 (en) 1997-05-05 2001-05-22 Abgenix, Inc. Human monoclonal antibodies to epidermal growth factor receptor
WO1998050433A2 (fr) 1997-05-05 1998-11-12 Abgenix, Inc. Anticorps monoclonaux humains contre le recepteur du facteur de croissance epidermique
WO1998050038A1 (fr) 1997-05-06 1998-11-12 American Cyanamid Company Utilisation de composes de la quinazoline dans le traitement de la maladie polykystique des reins
WO1999006396A1 (fr) 1997-07-29 1999-02-11 Warner-Lambert Company Inhibiteurs bicycliques irreversibles de tyrosine kinases
WO1999006378A1 (fr) 1997-07-29 1999-02-11 Warner-Lambert Company Inhibiteurs irreversibles de tyrosines kinases
WO1999009016A1 (fr) 1997-08-01 1999-02-25 American Cyanamid Company Derives de quinazoline substitues et leur utilisation en tant qu'inhibiteurs de la tyrosine kinase
WO1999024037A1 (fr) 1997-11-06 1999-05-20 American Cyanamid Company Traitement des polypes du colon par des inhibiteurs de la tyrosine kinase a base de derives de quinazoline
US6344455B1 (en) 1998-11-19 2002-02-05 Warner-Lambert Company N-[4-(3-chloro-4-fluoro-phenylamino)-7-(3-morpholin-4-yl-propoxy)-quinazolin-6-yl]-acrylamide, and irreversible inhibitor of tyrosine kinases
WO2006029879A2 (fr) 2004-09-17 2006-03-23 F.Hoffmann-La Roche Ag Anticorps anti-ox40l
WO2006105021A2 (fr) 2005-03-25 2006-10-05 Tolerrx, Inc. Molecules de liaison gitr et leurs utilisations
WO2006122150A1 (fr) 2005-05-10 2006-11-16 Incyte Corporation Modulateurs de l'indolamine 2,3-dioxygenase et leurs procedes d'utilisation
WO2007005874A2 (fr) 2005-07-01 2007-01-11 Medarex, Inc. Anticorps monoclonaux humains diriges contre un ligand de mort programmee de type 1(pd-l1)
WO2007075598A2 (fr) 2005-12-20 2007-07-05 Incyte Corporation N-hydroxyamidinoheterocycles en tant que modulateurs d'indoleamine 2,3-dioxygenase
WO2008036642A2 (fr) 2006-09-19 2008-03-27 Incyte Corporation N-hydroxyamidinohétérocycles en tant que modulateurs d'indoléamine 2,3-dioxygénase
WO2008036653A2 (fr) 2006-09-19 2008-03-27 Incyte Corporation N-hydroxyamidinohétérocycles modulateurs de l'indoléamine 2,3-dioxygénase
WO2008132601A1 (fr) 2007-04-30 2008-11-06 Immutep Anticorps monoclonal anti-lag-3 cytotoxique et son utilisation dans le traitement ou la prévention d'un rejet du greffon d'organe et de maladies auto-immunes
WO2009009116A2 (fr) 2007-07-12 2009-01-15 Tolerx, Inc. Thérapies combinées utilisant des molécules de liaison au gitr
WO2009044273A2 (fr) 2007-10-05 2009-04-09 Immutep Utilisation d'une protéine lag-3 recombinée ou de dérivés de celle-ci pour produire une réponse immunitaire des monocytes
WO2009073620A2 (fr) 2007-11-30 2009-06-11 Newlink Genetics Inhibiteurs de l'ido
WO2009115652A2 (fr) 2008-01-03 2009-09-24 Universite De La Mediterannee, Aix-Marseille Ii Composition et procedes utilisables lors d'un traitement anti-vih
WO2010019570A2 (fr) 2008-08-11 2010-02-18 Medarex, Inc. Anticorps humains qui se lient au gène 3 d'activation des lymphocytes (lag-3), et leurs utilisations
WO2010077634A1 (fr) 2008-12-09 2010-07-08 Genentech, Inc. Anticorps anti-pd-l1 et leur utilisation pour améliorer la fonction des lymphocytes t
WO2011028683A1 (fr) 2009-09-03 2011-03-10 Schering Corporation Anticorps anti-gitr
WO2011056652A1 (fr) 2009-10-28 2011-05-12 Newlink Genetics Dérivés imidazole comme inhibiteurs de l'ido
WO2011109400A2 (fr) 2010-03-04 2011-09-09 Macrogenics,Inc. Anticorps réagissant avec b7-h3, fragments immunologiquement actifs associés et utilisations associées
WO2012032433A1 (fr) 2010-09-09 2012-03-15 Pfizer Inc. Molécules de liaison 4-1bb
WO2012142237A1 (fr) 2011-04-15 2012-10-18 Newlink Geneticks Corporation Dérivés d'imidazole fusionnés pouvant être employés en tant qu'inhibiteurs d'ido
WO2012145493A1 (fr) 2011-04-20 2012-10-26 Amplimmune, Inc. Anticorps et autres molécules qui se lient à b7-h1 et à pd-1
WO2013079174A1 (fr) 2011-11-28 2013-06-06 Merck Patent Gmbh Anticorps anti-pd-l1 et utilisations associées
WO2014008218A1 (fr) 2012-07-02 2014-01-09 Bristol-Myers Squibb Company Optimisation d'anticorps se liant à la protéine lag-3 exprimée par le gène 3 d'activation des lymphocytes, et leurs utilisations
WO2014023708A1 (fr) * 2012-08-09 2014-02-13 F. Hoffmann-La Roche Ag Hétéro-azépinones substituées
WO2016139181A1 (fr) 2015-03-02 2016-09-09 Apeiron Biologics Ag Dérivés tétrahydrothiazépine bicycliques utiles pour le traitement de maladies infectieuses et/ou néoplasiques

Non-Patent Citations (26)

* Cited by examiner, † Cited by third party
Title
"Cancer Principles and Practice of Oncology", 15 February 2001, LIPPINCOTT WILLIAMS & WILKINS PUBLISHERS
"IUPAC - Compendium of Chemical Terminology", 1997, BLACKWELL SCIENTIFIC PUBLICATIONS
ANGEW CHEM. INTI. ED. ENGL, vol. 33, 1994, pages 183 - 186
ARRANZ-NICOLAS, J. AND MERIDA, I.: "Biological regulation of diacylglycerol kinases in normal and neoplastic tissues: New opportunities for cancer immunotherapy,", ADVANCES IN BIOLOGICAL REGULATION, vol. 75, 2020
ARRANZ-NICOLAS, JMERIDA, I: "Biological regulation of diacylglycerol kinases in normal and neoplastic tissues: New opportunities for cancer immunotherapy", ADVANCES IN BIOLOGICAL REGULATION, vol. 75, 2020
BARANYR. B. MERRIFIELD, J. AM. CHEM. SOC, vol. 99, 1977, pages 7363
CAS , no. 1627723-04-9
CAS, no. 1160430-89-6
H. WALDMANN ET AL., ANGEW. CHEM. INT. ED. ENGL, vol. 35, 1996, pages 2056
JOHNS ET AL., J. BIOL. CHEM, vol. 279, no. 29, 2004, pages 30375 - 30384
MA, QGABELLI, S.BRABEN, D.M: "Diacylglycerol kinases: relationship to other lipid kinases", ADV BIOL REGUL, vol. 71, 2019, pages 104 - 110, XP085582566, DOI: 10.1016/j.jbior.2018.09.014
MELLMAN, I ET AL.: "Cancer Immunotherapy Comes of Age", NATURE, vol. 480, no. 7378, 2011, pages 480 - 489, XP037922858, DOI: 10.1038/nature10673
MERIDA, IANDRADA, EGHARBI, S.IAVILA-FLORES, A: "Redundant and specialized roles for diacylglycerol kinases alpha and zeta in the control of T cell functions", SCI. SIGNAL, vol. 8, 2015, pages 374
MERIDA, IAVILA-FLORES, AMERINO, E: "Diacylglycerol kinases: at the hub of cell signalling", BIOCHEM. J, vol. 409, no. 1, 2008, pages 1 - 18
NOESSNER, E: "DGK-alpha: a checkpoint in cancer-mediated immuno-inhibition and target for immunotherapy", FRONT CELL DEV BIOL, vol. 5, 2017, pages 16
OLENCHOCK, B.AGUO, RCARPENTER, J.HJORDAN, M.TOPHAM, M.KKORETZKY, G.AZHONG, X.P: "Disruption of diacylglycerol metabolism impairs the induction of T cell anergy", NAT. IMMUNO, vol. 7, no. 11, 2006, pages 1174 - 1181
RICHARD C. LAROCK: "Comprehensive Organic Transformations: A Guide to Functional Group Preparations,", 1999, JOHN WILEY & SONS,
RIESE, M.JGREWAL, JDAS, JZOU, TPATIL, VCHAKRABORTY, A.KKORETZKY, G.A: "Decreased diacylglycerol metabolism enhances ERK activation and augments CD8+ T cell functional responses", J. BIOL. CHEM, vol. 286, no. 7, 2011, pages 5254 - 5265
RIESE, M.JMOON, E.KJOHNSON, B.DALBELDA, S.M: "Diacylglycerol kinases (DGKs): novel targets for improving T cell activity in cancer", FRONT CELL DEV BIOL, vol. 4, 2016, pages 108
SAKANE, FMIZUNO, SKOMENOI, S: "Diacylglycerol kinases as emerging potential drug targets for a variety of diseases: an update", FRONT CELL DEV BIOL, vol. 4, 2016, pages 82
SHULGA, Y.VTOPHAM, M.KEPAND, R.M: "Regulation and functions of diacylglycerol kinases", CHEM. REV., vol. 111, no. 10, 2011, pages 6186 - 6208
SIM, J.AKIM, JYANG, D: "Beyond Lipid Signaling: Pleiotropic Effects of Diacylglycerol Kinases in Cellular Signaling", INT. J. MOL. SCI, vol. 21, 2020, pages 6861
STRAGLIOTTO, CANCER, vol. 32, 1996, pages 636 - 640
T. W. GREENEP. G. M. WUTTS: "Protective Groups in Organic Chemistry", 2014, JOHN WILEY & SONS
TAKAHASHI, DSAKANE, F: "Expression and purification of human diacylglycerol kinase alpha from baculovirus-infected insect cells for structural studies", PEERJ, vol. 6, 2018, pages e5449
ZHA, YMARKS, RHO, A.WPETERSON, A.CANARDHAN, SBROWN, IPRAVEEN, KSTANG, S.STONE, J.CGAJEWSKI, T.F: "T cell anergy is reversed by active Ras and is regulated by diacylglycerol kinase-alpha", NAT. IMMUNOL, vol. 7, no. 11, 2006, pages 1166 - 1173, XP055916654, DOI: 10.1038/ni1394

Similar Documents

Publication Publication Date Title
US10022354B2 (en) Pyrrolidine amide compounds as histone demethylase inhibitors
EP2742040B1 (fr) Composes d'indazole, compositions pharmaceutiques et procedes d'utilisation de ceux-ci
US10035801B2 (en) Pyrazolo compounds and uses thereof
JP5822934B2 (ja) アザベンゾチアゾール化合物、組成物及び使用方法
JP2013542966A (ja) ピラゾロピリジンならびにｔｙｋ２阻害剤としてのピラゾロピリジン及びそれらの使用
KR20130001272A (ko) 이미다조피리딘 및 푸린 화합물, 조성물 및 사용 방법
WO2013007768A1 (fr) Composés hétérocycliques tricycliques, compositions et procédés d'utilisation de ces composés comme inhibiteurs des jak
WO2021086785A1 (fr) Composés bifonctionnels
WO2022171745A1 (fr) Dérivés bicycliques de tétrahydroazépine pour le traitement du cancer
US11787775B2 (en) Therapeutic compounds and methods of use
KR20240026948A (ko) 황 함유 헤테로방향족 트리사이클릭 kras 억제제
US10202354B2 (en) Therapeutic compounds and uses thereof
US10280149B2 (en) Therapeutic compounds and uses thereof
WO2015049325A1 (fr) Inhibiteurs thérapeutiques de cdk8 et utilisations de ceux-ci
WO2016091916A1 (fr) Pyrazolylaminopurines en tant qu'inhibiteurs de la tyrosyne kinase (itk)
WO2024033458A1 (fr) Dérivés bicycliques de tétrahydroazépine
WO2024033457A1 (fr) Dérivés bicycliques de tétrahydrothiazépine
WO2024033388A1 (fr) Dérivés bicycliques de tétrahydrothiazépine
WO2024033389A1 (fr) Dérivés bicycliques de tétrahydrothiazépine
TW202340212A (zh) 治療性化合物及其使用方法
CN116964048A (zh) 用于治疗癌症的双环四氢氮杂䓬衍生物
TW202400609A (zh) 三環吡啶酮及嘧啶酮

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23755359

Country of ref document: EP

Kind code of ref document: A1